Carboxylic acid derivative and a pharmaceutical composition containing the derivative as active ingredient

ABSTRACT

A peroxisome proliferator activated receptor regulator containing a compound of formula (I)  
                 
 
     (wherein all symbols are as defined in the specification), or a salt thereof as active ingredient.  
     Because of having an effect of regulating PPAR, a compound of formula (I) is useful as a hypoglycemic agent, a hypolipidemic agent, a preventive and/or a remedy for diseases associating metabolic disorders (diabetes, obesity, syndrome X, hypercholesterolemia, hyperlipoproteinemia, etc.), hyperlipemia, atherosclerosis, hypertension, circulatory diseases, overeating, coronary heart diseases, etc., an HDL cholesterol-elevating agent, an LDL cholesterol and/or VLDL cholesterol-lowering agent and a drug for relief from risk factors of diabetes or syndrome X.

TECHNICAL FIELD

[0001] The present invention relates to a carboxylic acid derivative anda peroxisome proliferator activated receptor regulator containingcarboxylic acid derivative as active ingredient.

[0002] More particularly, the present invention relates to a compound offormula (I)

[0003] (wherein all symbols are the same meanings as hereinafterdescribed), a non-toxic salt thereof and a hydrate thereof, a processfor the preparation thereof and a peroxisome proliferator activatedregulator containing thereof as active ingredient.

BACKGROUND

[0004] Recently in the study of transcription factors concerned withmarker genes expression in adipocytes differentiation, peroxisomeproliferator activated receptor (abbreviated as PPAR hereinafter), whichis one of intranuclear receptors, has been focused. cDNAs of PPAR werecloned from various kinds of animals, and plural isoform genes werefound, particularly in mammals three types of isoforms (α, δ, γ) areknown (see J. Steroid Biochem. Molec. Biol., 51, 157 (1994); GeneExpression,. 4, 281 (1995); Biochem Biophys. Res. Commun., 224, 431(1996); Mol. Endocrinology., 6, 1634 (1992)). PPARγ isoform ispredominantly expressed in adipose tissues, immune cells, adrenal gland,spleen, small intestine. PPARα isoform is mainly expressed in adiposetissue, liver, retina, and PPARδ isoform is widely expressed withoutspecificity for tissue (see Endocrinology., 137, 354 (1996)).

[0005] On the other hand, the following thiazolidine derivatives areknown as agents for the treatment of non-insulin dependent diabetesmellitus (NIDDM) and are hypoglycemic agents which are used for theimprovement of hyperglycemia in the patients suffering from diabetes.They are also effective for the improvement of hyperinsulinemia, glucosetolerance and decrease of serum lipid and therefore they are thought tobe considerably hopeful as agents for the treatment of insulinresistance.

[0006] One of the target proteins in the cells of these thiazolidinederivatives is exactly PPARγ and it is resolved that they enhance thetranscription activity of PPARγ (see Endocrinology., 13, 4189 (1996);Cell., 83, 803 (1995); Cell., 83, 813 (1995); J. Biol. Chem., 270, 12953(1995)). Therefore, a PPARγ activator (agonist) which enhances itstranscription activity is thought to be hopeful as a hypoglycemic agentand/or a hypolipidemic agent. Furthermore, since a PPARγ agonist isknown to promote the expression of PPARγ protein itself (Genes &Development., 10, 974 (1996)), an agent which increases the expressionof PPARγ protein itself as well as PPARγ activating agent is alsothought to be clinically useful.

[0007] Among all of nuclear receptors, PPARγ is related to adipocytesdifferentiation (see J. Biol. Chem., 272, 5637 (1997) and Cell., 83, 803(1995)). It is known that thiazolidine derivatives which activate thisreceptor promote adipocytes differentiation. Recently it was reportedthat thiazolidine derivatives increase fat mass and cause man to gainweight and to become obese (see Lancet., 349, 952 (1997)). Therefore, itis also thought that antagonists which inhibit PPARγ activity and agentsthat decrease the expression of PPARγ protein itself are also clinicallyapplicable. On the other hand, a compound that phosphorylates PPARγprotein and decreases its activity is reported (Science., 274, 2100(1996)). This implies that an agent which does not bind on PPARγ proteinas a ligand, but inhibits its activity is also clinically applicable.

[0008] From these, PPARγ activators (agonists) and PPARγ regulators forits expression that can increase the expression of the protein itselfare expected to be useful as hypoglycemic agents, hypolipidemic agents,and agents for prevention and/or treatment of diseases associated withmetabolic disorders such as diabetes, obesity, syndrome X,hypercholesterolemia and hyperlipoproteinemia etc., hyperlipidemia,atherosclerosis, hypertension, circulatory diseases and overeating etc.

[0009] On the other hand, antagonists that inhibit the transcriptionactivity of PPARγ or PPARγ regulators that inhibit the expression of theprotein itself are expected to be useful as hypoglycemic agents andagents for prevention and/or treatment of diseases associated withmetabolic disorders such as diabetes, obesity and syndrome X etc.,hyperlipidemia, atherosclerosis, hypertension and overeating etc.

[0010] The following fibrate compound (e.g. chlofibrate) is known as ahypolipidemic agent.

[0011] And, it is also resolved that one of the target proteins in thecells of fibrate compounds is PPARα (See Nature., 347, 645 (1990); J.Steroid Biochem. Molec. Biol., 51, 157 (1994); Biochemistry., 32, 5598(1993)). From these facts, PPARα regulators which can be activated byfibrate compounds are thought to have a hypolipidemic effect, and sothey are expected to be useful as agents for prevention and/or treatmentof hyperlipidemia etc.

[0012] Besides, it has been recently reported that PPAR a possessesanti-obese activity in the specification of WO 9736579. In addition, itwas reported that the elevation of high density lipoprotein (HDL)cholesterol level and the reduction of low density lipoprotein (LDL)cholesterol, very low density lipoprotein (VLDL) cholesterol andtriglyceride levels were induced by activation of PPARα (J. Lipid Res.,39, 17 (1998)). It was also reported that composition of fatty acids inblood, hypertension and insulin resistance were improved byadministration of bezafibrate which is one of fibtrate compounds(Diabetes., 46, 348 (1997)).

[0013] Therefore, agonists that activate PPARα and PPARα regulators thatpromote expression of PPARα protein itself are useful as hypolipidemicagents and agents for treatment of hyperlipidemia, and are expected tohave HDL cholesterol level-elevating effect, LDL cholesterol and/or VLDLcholesterol levels-lowering effect, inhibition on the progress ofatherosclerosis and anti-obese effect. Therefore, they are thought to behopeful agents for the treatment and/or prevention of diabetes ashypoglycemic agents, for the improvement of hypertension, for the relieffrom risk factor of syndrome X and for the prevention of occurrence ofischemic coronary diseases.

[0014] On the other hand, few reports are found on ligands that activatePPARδ significantly or on biological activities associated with PPAR δ.PPARδ is sometimes called PPARβ, or it is also called NUC1 in human.Until now, as for activity of PPARδ, it is disclosed in thespecification of WO 9601430 that hNUC1B (PPAR subtype whose structure isdifferent from that of human NUC1 in one amino acid) inhibited thetranscription activities of human PPARα and thyroid hormone receptor.Recently in the specification of WO 9728149, it was reported that thecompounds, which possessed high affinity to PPARδ protein and whichcould activate PPARδ significantly (i.e. agonists) were found out andthat they had HDL (high density lipoprotein) cholesterol level-elevatingactivity. Therefore, agonists that can activate PPARδ are expected tohave HDL cholesterol level-elevating effect, and so they are expected tobe useful for the inhibition on the progress of atherosclerosis andtreatment thereof, as hypolipidemic agents and hypoglycemic agents, forthe treatment of hyperlipidemia, as hypoglycemic agents, for thetreatment of diabetes, for the relief from risk factor of syndrome X,and for the prevention of occurrence of ischemic coronary diseases.

[0015] As for PPAR regulators, the following compounds were reportedbesides the above-mentioned thiazolidine derivatives and fibratecompounds.

[0016] For example, in WO9731907, it is disclosed that the compounds offormula (A)

[0017] (wherein A^(A) is phenyl, in which the said phenyl may besubstituted with one or more substituent(s) selected from groupconsisting of halogen, C1-6 alkyl, C1-3 alkoxy, C1-3 fluoroalkoxy,nitrile or —NR^(7A)R^(8A) (R^(7A) and R^(8A) each independently, ishydrogen or C1-3 alkyl);

[0018] B^(A) is (5- or 6-membered heterocyclic ring containing at leastone hetero atom selected from O, N and S)—C1-6 alkylene-, in which thesaid heterocyclic ring may be substituted with C1-3 alkyl;

[0019] Alk^(A) is C1-3 alkylene;

[0020] R^(1A) is hydrogen or C1-3 alkyl;

[0021] Z^(A) is —(C1-3 alkylene)phenyl or —NR^(3A)R^(4A)) orpharmaceutically acceptable salts thereof possess PPARγ agonist activity(the necessary parts in explanation of symbols are shown).

[0022] On the other hand, in JP-A-9-323982, it is disclosed that thepropionic acid derivatives of formula (B)

[0023] (wherein R^(B) is

[0024] (wherein R^(′B) is substituted or unsubstituted aromatichydrocarbon, substituted or unsubstituted aliphatic hydrocarbon ring,substituted or unsubstituted heterocyclic ring or substituted orunsubstituted condensed heterocyclic ring, R^(5B) is lower alkyl),R^(4B) is hydrogen or lower alkyl, R^(6B) is hydrogen or R^(6B) andR^(9B) taken together form double bond, R^(7B) is hydrogen, hydroxy,carboxy, acyl, substituted or unsubstituted alkoxycarbonyl, substitutedor unsubstituted lower alkyl, substituted or unsubstituted carbamoyl,substituted or unsubstituted aryloxycarbonyl, substituted orunsubstituted aralkyloxycarbonyl or —Y^(B)—R^(8B) (in which Y^(B) is—NH— or O, R^(8B) is substituted or unsubstituted acyl, substituted orunsubstituted alkoxycarbonyl, aryloxycarbonyl or aralkyloxycarbonyl),R^(9B) is hydrogen, substituted or unsubstituted lower alkyl orsubstituted or unsubstituted lower alkoxycarbonyl, R^(10B) is hydroxy,substituted or unsubstituted amino, substituted or unsubstituted loweralkoxy, substituted or unsubstituted lower alkyl, substituted orunsubstituted aryloxy or substituted or unsubstituted aralkyloxy)

[0025] or pharmaceutically acceptable salts thereof possess hypoglycemicaction and hypolipidemic action. In addition, JP-A-8-325264,JP-A-8-325250, WO9638415 and WO9800137 have also disclosed thatanalogous compounds possess hypoglycemic action and hypolipidemicaction.

[0026] In JP-A-5-507920, it is disclosed that the compound of formula(C)

[0027] (wherein A^(C) is

[0028] ------ represents bond or not represents bond;

[0029] R^(C) is C1˜C8 alkyl, C3˜C7 cycloalkyl, C3˜C8 alkenyl, C3˜8alkynyl, phenyl,

[0030] C7˜C8 phenylalkyl, C2˜C8 alkanoyl, or one of above groupssubstituted by one or two of C1˜C3 alkyl, trifluoromethyl, hydroxy,C1˜C3 alkoxy, fluoride or chloride;

[0031] X^(C) is S, O, NR^(2C), —CH═CH—, —CH═N— or —N═CH;

[0032] R^(2C) is hydrogen, C1˜C3 alkyl, phenyl or benzyl;

[0033] Y^(C) is CH or N;

[0034] Z^(C) is hydrogen, C1˜C7 alkyl, C3˜C7 cycloalkyl, phenyl, orphenyl, substituted by one or two of C1˜C3 alkyl, trifluoromethyl, C1˜C3alkoxy, phenyl, phenoxy, benzyl, benzyloxy, fluoride or chloride;

[0035] X^(′C) is O, S, SO or SO₂;

[0036] Y^(′C) is hydroxy, C1˜C3 alkoxy;

[0037] Z^(′C) is hydrogen or C1˜C3 alkyl.) possess hypoglycemic actionand hypolipidemic action.

[0038] J. Med. Chem., 39, 3897 (1996) have also disclosed that analogouscompounds possess hypoglycemic action and hypolipidemic action, thecompound of formula (D) is disclosed.

DISCLOSURE OF THE INVENTION

[0039] As the result of energetic investigations in order to findcompounds possessing regulating action on PPAR, the present inventorshave found that the purpose has been accomplished by the compound offormula (I) and have completed the present invention.

[0040] The present invention relates to

[0041] (1) a compound of formula (I)

[0042] (wherein R¹ independently, is hydrogen, C1˜8 alkyl, halogen, C1˜4alkoxy, C1˜4 alkoxy, C1˜4 alkylthio, nitro, NR⁴R⁵ (in which R⁴ and R⁵each independently, is C1˜4 alkyl.), cyano, trifluoromethyl,trifluoromethyloxy, carbocyclic ring or hetero ring (carbocyclic ringand hetero ring are optionally substituted by group selected from C1˜4alkyl, C1˜4 alkoxy, halogen or trifluoromethyl.),

[0043] R² is hydrogen, C1˜8 alkyl, halogen, C1˜4 alkoxy, C1˜4 alkylthio,nitro, NR⁴R⁵ (in which R⁴ and R⁵ each independently, is C1˜4 alkyl.),cyano, trifluoromethyl or trifluoromethyloxy,

[0044] R³ is hydrogen or C1˜4 alkyl,

[0045] X¹ is —N— or —CH—

[0046] X² and Y each independently, is —O—, —S— or —NR⁶— (in which R⁶ ishydrogen or C1˜4 alkyl.),

[0047] Z is —O— or —S(O)_(p)— (in which p is 0, 1 or 2),

[0048] R⁷ and R⁸ each independently, is hydrogen or C1˜4 alkyl, or R⁷and R⁸ taken together with carbon atom to which is attached representsC3˜7 cycloalkylene,

[0049] is carbocyclic ring or hetero ring,

[0050] is double bond or triple bond,

[0051] m and n each independently, is 1˜3.)

[0052] a non-toxic salt thereof, or a hydrate thereof,

[0053] (2) a peroxisome proliferator activated receptor regulatorcontaining a compound of formula (I), a non-toxic salt thereof, or ahydrate thereof as active ingredient, and

[0054] (3) a process for the preparation of a compound of formula (I).

DETAILED EXPLANATION

[0055] Unless otherwise specified, all isomers are included in thepresent invention. For example, alkyl, alkoxy and alkylthio groupincludes straight or branched ones. In addition, isomers on double bond,ring, fused ring (E-, Z-, cis-, trans-isomer), isomers generated fromasymmetric carbon atom(s) (R-, S-, α-, β-isomer, enantiomer,diastereomer), optically active isomers (D-, L-, d-, I-isomer), polarcompounds generated by chromatographic separation (more polar compound,less polar compound), equilibrium compounds, mixtures thereof atvoluntary ratios and racemic mixtures are also included in the presentinvention.

[0056] In the formula (I), C1˜8 alkyl represented by R¹ and R² meansmethyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and isomersthereof.

[0057] In the formula (I), C1˜4 alkyl represented by R³, R⁴, R⁵, R⁶, R⁷and R⁸, or C1˜4 alkyl as a substituent of carbocyclic ring or heteroring represented by R¹, means methyl, ethyl, propyl, butyl and isomersthereof.

[0058] In the formula (I), C1˜4 alkoxy represented by R¹ and R², or C1˜4alkoxy as a substituent of carbocyclic ring or hetero ring representedby R¹, means methoxy, ethoxy, propoxy, butoxy and isomers thereof.

[0059] In the formula (I), C1˜4 alkylthio represented by R¹ and R² meansmethylthio, ethylthio, propylthio, butylthio and isomers thereof.

[0060] In the formula (I), halogen represented by R¹ and R², or halogenas a substituent of carbocyclic ring or hetero ring represented by R¹,means fluoride, chloride, bromide and iodide.

[0061] In the formula (I), C3˜7 cycloalkylene represented by R⁷ and R⁸taken together with carbon atom to which is attached meanscyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene andcycloheptylene.

[0062] In the formula (I), carbocyclic ring represented by R¹ and

[0063] means C3˜10 mono-, or bi-cyclic carbocyclic ring and bridgedcarbocyclic ring. For example, C3-10 mono-, or bi-cyclic carbocyclicring and bridged carbocyclic ring means cyclopropane, cyclobutane,cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane,cyclodecane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene,benzene, pentalene, indene, naphthalene, azulene, dihydronaphthalene,tetrahydronaphthalene, perhydronaphthalene, indane (dihydroindene),perhydroindene, bicyclopentane, bicyclohexane, bicycloheptane([2.2.1]bicycloheptane), bicyclooctane, bicyclononane, bicyclodecane,adamantane etc.

[0064] In the formula (I), hetero ring represented by R¹ and

[0065] means unsaturated, or partially or completely saturated, 5˜15membered mono- or bi-cyclic hetero ring containing 1˜3 of nitrogenatom(s), 1˜2 of oxygen atom(s) and/or one sulfur atom. For example,unsaturated, or partially or completely saturated, 5˜15 membered mono-or bi-cyclic hetero ring containing 1˜3 of nitrogen atom(s), 1˜2 ofoxygen atom(s) and/or one sulfur atom, mean pyrroline, pyrrolidine,imidazoline, imidazolidine, pyrazoline, pyrazolidine, piperidine,piperazine, tetrahydropyrimidine, hexahydropyrimidine,tetrahydropyridazine, hexahydropyridazine, hexahydroazepine,dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran,dihydrothiophene, tetrahydrothiophene, dihydrothiine (dihydrothiopyran),tetrahydrothiine (tetrahydrothiopyran), dihydrooxazole,tetrahydrooxazole, dihydroisoxazole, tetrahydroisoxazole,dihydrothiazole, tetrahydrothiazole, dihydroisothiazole,tetrahydroisothiazole, morpholine, thiomorpholine, indoline,isoindoline, dihydroindazole, perhydroindazole, dihydroquinoline,tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline,tetrahydroisoquinoline, perhydroisoquinoline, dihydrophthalazine,tetrahydrophthalazine, perhydrophthalazine, dihydronaphthyridine,tetrahydronaphthyridine, perhydronaphthyridine, dihydroquinoxaline,tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazoline,tetrahydroquinazoline, perhydroquinazoline, dihydrocinnoline,tetrahydrocinnoline, perhydrocinnoline, dihydrobenzoxazole,perhydrobenzoxazole, dihydrobenzothiazole, perhydrobenzothiazole,dihydrobenzimidazole, perhydrobenzimidazole, dihydrobenzoxazine,dioxaindan (1,3-dioxaindan), benzodioxane, quinuclidine, pyrrole,imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine,azepine, diazepine, furan, pyran, oxepine, oxazepine, thiophene, thiin(thiopyran), thiepin, oxazole, isoxazole, thiazole, isothiazole,oxadiazole, oxazine, oxadiazine, oxazepine, oxadiazepine, thiadiazole,thiazine, thiadiazine, thiazepine, thiadiazepine, indole, isoindole,benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, indazole,quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline,quinazoline, cinnoline, benzoxazole, benzothiazole, benzimidazole,oxatetrahydrofuran, imidazopyridine, benzotriazole etc.

[0066] In the compounds of formula (I), all groups represented by X¹ arepreferable, and more preferable group is —N—.

[0067] In the compounds of formula (I), all groups represented by X² arepreferable, and more preferable group is —O—.

[0068] In the compounds of formula (I), all groups represented by Y arepreferable, and more preferable group is —O— or —S—, and most preferablegroups is —O—.

[0069] In the compounds of formula (I), all groups represented by Z arepreferable, and more preferable group is —S—, —SO—, or —SO₂—, and mostpreferable groups is —S—.

[0070] In the compounds of formula (I), 1˜3 represented by n are allpreferable, and more preferable is 1.

[0071] In the compounds of formula (I), all groups represented by

[0072] are preferable, and more preferable group is double bond.Furthermore, preferable group is double bond of trans form.

[0073] In the compounds of formula (I), all groups represented by

[0074] are preferable, and more preferable group is unsaturated, orpartially or completely saturated, 5˜10 membered mono- or bi-cyclichetero ring containing 1˜2 of nitrogen atom(s), 1˜2 of oxygen atom(s)and/or one sulfur atom. Furthermore, preferable groups are cyclopentane,cyclohexane, cycloheptane, benzene, furan, thiophene, pyridine,quinoline, dioxaindan (e.g. 1,3-dioxaindan).

[0075] In the present invention, PPAR regulator includes all theregulators of PPARα, γ, δ, α+γ, α+δ, γ+δ and α+γ+δ. Preferableregulatory fashion is, PPARα regulator, PPARγ regulator, PPARδregulator, PPARα+γ regulator, PPARα+δ regulator, more preferably PPARα+γregulator. PPAR regulator also includes PPAR agonist and PPARantagonist, preferably PPAR agonist, more preferably PPARα agonist,PPARγ agonist, PPARδ agonist, PPARα+γ agonist or PPARα+δ agonist,particularly preferably PPARα+γ agonist.

[0076] Among the compounds of formula (I), preferable ones are, acompound of formula (Ia)

[0077] (wherein all symbols are the same meanings as hereinbeforedescribed.), a compound of formula (Ib)

[0078] (wherein all symbols are the same meanings as hereinbeforedescribed.), a compound of formula (Ic)

[0079] (wherein all symbols are the same meanings as hereinbeforedescribed.), a compound of formula (Id)

[0080] (wherein all symbols are the same meanings as hereinbeforedescribed.), a compound of formula (Ie)

[0081] (wherein all symbols are the same meanings as hereinbeforedescribed.), a compound of formula (If)

[0082] (wherein all symbols are the same meanings as hereinbeforedescribed.), a

[0083] (wherein all symbols are the same meanings as hereinbeforedescribed.), a compound of formula (Ih)

[0084] (wherein all symbols are the same meanings as hereinbeforedescribed.), a non-toxic salts thereof, or a hydrate thereof.

[0085] Concrete compounds are the compounds shown in the followingTables 1˜24, a non-toxic salts thereof and a hydrate thereof, andcompounds described in Example hereinafter.

[0086] In the each Table, Me is methyl, Et is ethyl, n-Pr isnormalpropyl, n-But is normalbutyl and the other symbols are the samemeanings as hereinbefore described. TABLE 1 (Ia-1)

No. (R¹)_(m) 1 H 2 4-Me 3 4-Et 4 4-n-Pr 5 4-n-but 6 4-F 7 4-Cl 8 4-CF₃ 94-CF₃O 10 4-MeS 11 4-MeO 12 4-NO₂ 13 4-CN 14 3-Me 15 3-Et 16 3-n-Pr 173-n-but 18 3-F 19 3-Cl 20 3-CF₃ 21 3-CF₃O 22 3-MeS 23 3-MeO 24 3-NO₂ 253-CN 26 3,4-di-MeO

[0087] TABLE 2 (Ia-2)

No. (R¹)_(m) 1 H 2 4-Me 3 4-Et 4 4-n-Pr 5 4-n-but 6 4-F 7 4-Cl 8 4-CF₃ 94-CF₃O 10 4-MeS 11 4-MeO 12 4-NO₂ 13 4-CN 14 2-Me 15 2-Et 16 2-n-Pr 172-n-but 18 2,2-di-Me 19 2,2-di-Et 20 2-F 21 2-Cl 22 2,2-di-F 232,2-di-Cl

[0088] TABLE 3 (Ia-3)

No. (R¹)_(m) 1 H 2 4-Me 3 4-Et 4 4-n-Pr 5 4-n-but 6 4-F 7 4-Cl 8 4-CF₃ 94-CF₃O 10 4-MeS 11 4-MeO 12 4-NO₂ 13 4-CN 14 3-Me 15 3-Et 16 3-n-Pr 173-n-but 18 3-F 19 3-Cl 20 3-CF₃ 21 3-CF₃O 22 3-MeS 23 3-MeO 24 3-NO₂ 253-CN 26 3,4-di-MeO

[0089] TABLE 4 (Ib-1)

No. (R²)_(m) 1 H 2 4-Me 3 4-Et 4 4-n-Pr 5 4-n-but 6 4-F 7 4-Cl 8 4-CF₃ 94-CF₃O 10 4-MeS 11 4-MeO 12 4-NO₂ 13 4-CN 14 3-Me 15 3-Et 16 3-n-Pr 173-n-but 18 3-F 19 3-Cl 20 3-CF₃ 21 3-CF₃O 22 3-MeS 23 3-MeO 24 3-NO₂ 253-CN 26 3,4-di-MeO

[0090] TABLE 5 (Ib-2)

No. (R¹)_(m) 1 H 2 4-Me 3 4-Et 4 4-n-Pr 5 4-n-but 6 4-F 7 4-Cl 8 4-CF₃ 94-CF₃O 10 4-MeS 11 4-MeO 12 4-NO₂ 13 4-CN 14 2-Me 15 2-Et 16 2-n-Pr 172-n-but 18 2,2-di-Me 19 2,2-di-Et 20 2-F 21 2-Cl 22 2,2-di-F 232,2-di-Cl

[0091] TABLE 6 (Ib-3)

No. (R¹)_(m) 1 H 2 4-Me 3 4-Et 4 4-n-Pr 5 4-n-but 6 4-F 7 4-Cl 8 4-CF₃ 94-CF₃O 10 4-MeS 11 4-MeO 12 4-NO₂ 13 4-CN 14 3-Me 15 3-Et 16 3-n-Pr 173-n-but 18 3-F 19 3-Cl 20 3-CF₃ 21 3-CF₃O 22 3-MeS 23 3-MeO 24 3-NO₂ 253-CN 26 3,4-di-MeO

[0092] TABLE 7 (Ic-1)

No. (R¹)_(m) 1 H 2 4-Me 3 4-Et 4 4-n-Pr 5 4-n-but 6 4-F 7 4-Cl 8 4-CF₃ 94-CF₃O 10 4-MeS 11 4-MeO 12 4-NO₂ 13 4-CN 14 3-Me 15 3-Et 16 3-n-Pr 173-n-but 18 3-F 19 3-Cl 20 3-CF₃ 21 3-CF₃O 22 3-MeS 23 3-MeO 24 3-NO₂ 253-CN 26 3,4-di-MeO

[0093] TABLE 8 (Ic-2)

No. (R¹)_(m) 1 H 2 4-Me 3 4-Et 4 4-n-Pr 5 4-n-but 6 4-F 7 4-Cl 8 4-CF₃ 94-CF₃O 10 4-MeS 11 4-MeO 12 4-NO₂ 13 4-CN 14 2-Me 15 2-Et 16 2-n-Pr 172-n-but 18 2,2-di-Me 19 2,2-di-Et 20 2-F 21 2-Cl 22 2,2-di-F 232,2-di-Cl

[0094] TABLE 9 (Ic-3)

No. (R¹)_(m) 1 H 2 4-Me 3 4-Et 4 4-n-Pr 5 4-n-but 6 4-F 7 4-Cl 8 4-CF₃ 94-CF₃O 10 4-MeS 11 4-MeO 12 4-NO₂ 13 4-CN 14 3-Me 15 3-Et 16 3-n-Pr 173-n-but 18 3-F 19 3-Cl 20 3-CF₃ 21 3-CF₃O 22 3-MeS 23 3-MeO 24 3-NO₂ 253-CN 26 3,4-di-MeO

[0095] TABLE 10 (Id-1)

No. (R¹)_(m) 1 H 2 4-Me 3 4-Et 4 4-n-Pr 5 4-n-but 6 4-F 7 4-Cl 8 4-CF₃ 94-CF₃O 10 4-MeS 11 4-MeO 12 4-NO₂ 13 4-CN 14 3-Me 15 3-Et 16 3-n-Pr 173-n-but 18 3-F 19 3-Cl 20 3-CF₃ 21 3-CF₃O 22 3-MeS 23 3-MeO 24 3-NO₂ 253-CN 26 3,4-di-MeO

[0096] TABLE 11 (Id-2)

No. (R¹)_(m) 1 H 2 4-Me 3 4-Et 4 4-n-Pr 5 4-n-but 6 4-F 7 4-Cl 8 4-CF₃ 94-CF₃O 10 4-MeS 11 4-MeO 12 4-NO₂ 13 4-CN 14 2-Me 15 2-Et 16 2-n-Pr 172-n-but 18 2,2-di-Me 19 2,2-di-Et 20 2-F 21 2-Cl 22 2,2-di-F 232,2-di-Cl

[0097] TABLE 12 (Id-3)

No. (R¹)_(m) 1 H 2 4-Me 3 4-Et 4 4-n-Pr 5 4-n-but 6 4-F 7 4-Cl 8 4-CF₃ 94-CF₃O 10 4-MeS 11 4-MeG 12 4-NO₂ 13 4-CN 14 3-Me 15 3-Et 16 3-n-Pr 173-n-but 18 3-F 19 3-Cl 20 3-CF₃ 21 3-CF₃O 22 3-MeS 23 3-MeO 24 3-NO₂ 253-CN 26 3,4-di-MeO

[0098] TABLE 13 (Ie-1)

No. (R¹)_(m) 1 H 2 4-Me 3 4-Et 4 4-n-Pr 5 4-n-but 6 4-F 7 4-Cl 8 4-CF₃ 94-CF₃O 10 4-MeS 11 4-MeO 12 4-NO₂ 13 4-CN 14 3-Me 15 3-Et 16 3-n-Pr 173-n-but 18 3-F 19 3-Cl 20 3-CF₃ 21 3-CF₃O 22 3-MeS 23 3-MeO 24 3-NO₂ 253-CN 26 3,4-di-MeO

[0099] TABLE 14 (Ie-2)

No. (R¹)_(m) 1 H 2 4-Me 3 4-Et 4 4-n-Pr 5 4-n-but 6 4-F 7 4-Cl 8 4-CF₃ 94-CF₃O 10 4-MeS 11 4-MeO 12 4-NO₂ 13 4-CN 14 2-Me 15 2-Et 16 2-n-Pr 172-n-but 18 2,2-di-Me 19 2,2-di-Et 20 2-F 21 2-Cl 22 2,2-di-F 232,2-di-Cl

[0100] TABLE 15 (Ie-3)

No. (R¹)_(m) 1 H 2 4-Me 3 4-Et 4 4-n-Pr 5 4-n-but 6 4-F 7 4-Cl 8 4-CF₃ 94-CF₃O 10 4-MeS 11 4-MeO 12 4-NO₂ 13 4-CN 14 3-Me 15 3-Et 16 3-n-Pr 173-n-but 18 3-F 19 3-Cl 20 3-CF₃ 21 3-CF₃O 22 3-MeS 23 3-MeO 24 3-NO₂ 253-CN 26 3,4-di-MeO

[0101] TABLE 16 (If-1)

No. (R¹)_(m) 1 H 2 4-Me 3 4-Et 4 4-n-Pr 5 4-n-but 6 4-F 7 4-Cl 8 4-CF₃ 94-CF₃O 10 4-MeS 11 4-MeO 12 4-NO₂ 13 4-CN 14 3-Me 15 3-Et 16 3-n-Pr 173-n-but 18 3-F 19 3-Cl 20 3-CF₃ 21 3-CF₃O 22 3-MeS 23 3-MeO 24 3-NO₂ 253-CN 26 3,4-di-MeO

[0102] TABLE 17 (If-2)

No. (R¹)_(m) 1 H 2 4-Me 3 4-Et 4 4-n-Pr 5 4-n-but 6 4-F 7 4-Cl 8 4-CF₃ 94-CF₃O 10 4-MeS 11 4-MeO 12 4-NO₂ 13 4-CN 14 2-Me 15 2-Et 16 2-n-Pr 172-n-but 18 2,2-di-Me 19 2,2-di-Et 20 2-F 21 2-Cl 22 2,2-di-F 232,2-di-Cl

[0103] TABLE 18 (If-3)

No. (R¹)_(m) 1 H 2 4-Me 3 4-Et 4 4-n-Pr 5 4-n-but 6 4-F 7 4-Cl 8 4-CF₃ 94-CF₃O 10 4-MeS 11 4-MeO 12 4-NO₂ 13 4-CN 14 3-Me 15 3-Et 16 3-n-Pr 173-n-but 18 3-F 19 3-Cl 20 3-CF₃ 21 3-CF₃O 22 3-MeS 23 3-MeO 24 3-NO₂ 253-CN 26 3,4-di-MeO

[0104] TABLE 19 (Ig-1)

No. (R¹)_(m) 1 H 2 4-Me 3 4-Et 4 4-n-Pr 5 4-n-but 6 4-F 7 4-Cl 8 4-CF₃ 94-CF₃O 10 4-MeS 11 4-MeO 12 4-NO₂ 13 4-CN 14 3-Me 15 3-Et 16 3-n-Pr 173-n-but 18 3-F 19 3-Cl 20 3-CF₃ 21 3-CF₃O 22 3-MeS 23 3-MeO 24 3-NO₂ 253-CN 26 3,4-di-MeO

[0105] TABLE 20 (Ig-2)

No. (R¹)_(m) 1 H 2 4-Me 3 4-Et 4 4-n-Pr 5 4-n-but 6 4-F 7 4-Cl 8 4-CF₃ 94-CF₃O 10 4-MeS 11 4-MeO 12 4-NO₂ 13 4-CN 14 2-Me 15 2-Et 16 2-n-Pr 172-n-but 18 2,2-di-Me 19 2,2-di-Et 20 2-F 21 2-Cl 22 2,2-di-F 232,2-di-Cl

[0106] TABLE 21 (Ig-3)

No. (R¹)_(m) 1 H 2 4-Me 3 4-Et 4 4-n-Pr 5 4-n-but 6 4-F 7 4-Cl 8 4-CF₃ 94-CF₃O 10 4-MeS 11 4-MeO 12 4-NO₂ 13 4-CN 14 3-Me 15 3-Et 16 3-n-Pr 173-n-but 18 3-F 19 3-Cl 20 3-CF₃ 21 3-CF₃O 22 3-MeS 23 3-MeO 24 3-NO₂ 253-CN 26 3,4-di-MeO

[0107] TABLE 22 (Ih-1)

No. (R¹)_(m) 1 H 2 4-Me 3 4-Et 4 4-n-Pr 5 4-n-but 6 4-F 7 4-Cl 8 4-CF₃ 94-CF₃O 10 4-MeS 11 4-MeO 12 4-NO₂ 13 4-CN 14 3-Me 15 3-Et 16 3-n-Pr 173-n-but 18 3-F 19 3-Cl 20 3-CF₃ 21 3-CF₃O 22 3-MeS 23 3-MeO 24 3-NO₂ 253-CN 26 3,4-di-MeO

[0108] TABLE 23 (Ih-2)

No. (R¹)_(m) 1 H 2 4-Me 3 4-Et 4 4-n-Pr 5 4-n-but 6 4-F 7 4-Cl 8 4-CF₃ 94-CF₃O 10 4-MeS 11 4-MeO 12 4-NO₂ 13 4-CN 14 2-Me 15 2-Et 16 2-n-Pr 172-n-but 18 2,2-di-Me 19 2,2-di-Et 20 2-F 21 2-Cl 22 2,2-di-F 232,2-di-Cl

[0109] TABLE 24 (Ih-3)

No. (R¹)_(m) 1 H 2 4-Me 3 4-Et 4 4-n-Pr 5 4-n-but 6 4-F 7 4-Cl 8 4-CF₃ 94-CF₃O 10 4-MeS 11 4-MeO 12 4-NO₂ 13 4-CN 14 3-Me 15 3-Et 16 3-n-Pr 173-n-but 18 3-F 19 3-Cl 20 3-CF₃ 21 3-CF₃O 22 3-MeS 23 3-MeO 24 3-NO₂ 253-CN 26 3,4-di-MeO

[0110] [Process for the Preparation of the Compound of the PresentInvention]

[0111] (a) In the compound of formula (I), the compound wherein Z is—O—, —S—, and R³ is C1˜4 alkyl, i.e., the compound of formula (I-A)

[0112] (wherein Z¹ is —O—, —S—, R³⁻¹ is C1˜4 alkyl, the other symbolsare the same meanings as hereinbefore described.) may be prepared byreacting the compound of formula (II)

[0113] (wherein R⁹ is methanesulfonyloxy or halogen, the other symbolsare the same meanings as hereinbefore described.) with the compound offormula (III)

[0114] (wherein Z¹⁻¹ is —OH or —SH, the other symbols are the samemeanings as hereinbefore described.).

[0115] This reaction is known, for example, may be carried out in anorganic solvent (tetrahydrofuran (THF), diethylether, dichloromethane,chloroform, carbon tetrachloride, pentane, hexane, benzene, toluene,dimethylformamide (DMF), dimethylsulfoxide (DMSO),hexamethylphosphoramide (HMPA) etc.), in the presence of base (sodiumhydroxide, potassium carbonate, triethylamine, pyridine, sodium iodide,cesium carbonate etc.) at 0˜80° C.

[0116] (b) In the compound of formula (I), the compound wherein Z is—O—, —S—, and R³ is hydrogen, i.e., the compound of formula (I-B)

[0117] (wherein all symbols are the same meaning as hereinbeforedescribed.) may be prepared by hydrolysis reaction of the compound offormula (I-A).

[0118] The said hydrolysis reaction is known, for example, may becarried out

[0119] (1) in an organic solvent admissible with water (THF, dioxane,ethanol, methanol etc.) or mixture solvent thereof, using an aqueoussolution of alkali (potassium hydroxide, sodium hydroxide, potassiumcarbonate, sodium carbonate etc.), or

[0120] (2) in alkanol (methanol, ethanol etc.), using the above alkaliunder an anhydrous condition. These reactions may be carried out at0˜100° C. normally.

[0121] (c) In the compound of formula (I), p is 1 or 2, namely, Z is—SO—) or —SO₂—, i.e., the compound of formula (I-C)

[0122] (wherein Z² is —SO— or —SO₂—, the other symbols are the samemeanings as hereinbefore described.) may be prepared by oxidation of thecompound of formula (I-A) or formula (I-B) wherein Z¹ is —S—.

[0123] The compound of formula (I-C) wherein Z² is —SO₂—, may be alsoprepared by oxidation of the compound of formula (I-C) wherein Z² is—SO—.

[0124] This oxidation is known, for example, may be carried out in anorganic solvent (THF, dichloromethane, chloroform etc.), using anecessary amount of oxidizing agent (perhydrogen oxide, sodiumperiodate, acyl nitrite, sodium perboronate, peracid (e.g.,3-chloroperbenzoic acid, peracetic acid, OXONE (trade mark)) etc.) at0˜50° C.

[0125] The compounds of formulae (II) and (III) are known per se or maybe prepared by known methods.

[0126] For example, in the compound of formula (III), 2-mercaptoaceticacid.methyl ester (thioglycolic acid methyl) has been marketed.

[0127] For example, the compound of formula (II) may be preparedaccording to the following Schemes 1˜2.

[0128] In each Scheme, the abbreviation and symbols are as the followingmeanings, and the other symbols are the same meanings as hereinbeforedescribed.

[0129] Me: methyl,

[0130] Bu: n-butyl,

[0131] R¹⁰: halogen,

[0132] Pd(PPh₃)₄: tetrakis(triphenylphosphine)palladium,

[0133] n′: 0˜2,

[0134] R¹¹: C˜14 alkyl.

[0135]

[0136] The compounds of formulae (IV), (VII), (XI) and (XV) are knownper se or may be prepared by known methods.

[0137] The reactions described in the above-mentioned Schemes may becarried out by known methods.

[0138] In the present invention, the other starting materials and eachreagent are known per se or may be prepared by known methods.

[0139] In each reaction in the present specification, products may bepurified by a conventional manner. For example, it may be carried out bydistillation at atmospheric or reduced pressure, high performance liquidchromatography, thin layer chromatography or column chromatography usingsilica gel or magnesium silicate, washing or recrystallization.Purification may be carried out after each reaction or after a series ofreactions.

[0140] All the non-toxic salts are also included in the presentinvention. For example, the compounds of the formula (I) of the presentinvention may be converted into the corresponding salts by knownmethods. Non-toxic and water-soluble salts are preferable. Suitablesalts, for example, are follows:

[0141] salts of alkaline metals (potassium, sodium etc.), salts ofalkaline earth metals (calcium, magnesium etc.), ammonium salts, saltsof pharmaceutically acceptable organic amines (tetramethylammonium,triethylamine, methylamine, dimethylamine, cyclopentylamine,cyclohexylamine, benzylamine, phenethylamine, piperidine,monoethanolamine, diethanolamine, tris(hydroxymethyl)amine, lysine,arginine, N-methyl-D-glucamine etc.).

[0142] The compounds of formula (I) of the present invention may beconverted into the corresponding acid additional salts by methods knownper se. Non-toxic and water-soluble acid addition salts are preferable.Suitable acid addition salts, for example, are salts of inorganic acids,e.g., hydrochloride, hydrobromide, sulphate, phosphate, nitrate etc., orsalts of organic acids, e.g., acetate, trifluoroacetate, lactate,tartarate, oxalate, fumarate, maleate, citrate, benzoate,methanesulphonate, ethanesulphonate, benzenesulphonate,toluenesulphonate, isethioate, glucuronate, gluconate etc.

[0143] The compounds of formula (I) of the present invention or saltsthereof may be converted into hydrate thereof by methods known per se.

[0144] [Pharmacological Activity]

[0145] It was confirmed that a compound of the present invention offormula (I) has PPAR regulating activities by the following experiments.

[0146] Measurement of PPARα Agonistic and PPARγ Agonistic Activities

[0147] (1) Preparation of Materials in Luciferase Assay Using HumanPPARα or δ

[0148] The whole operations were carried out by the basic methods ingene engineering techniques and the conventional methods in yeastOne-hybrid or Two-hybrid system.

[0149] As a luciferase gene expression vector under the control ofthymidine kinase (TK) promotor, luciferase structural gene was excisedfrom PicaGene Basic Vector 2 (trade name, Toyo Ink Inc., catalogue No.309-04821), to prepare luciferase gene expression vector pTK-Luc. underthe control of TK promotor (−105/+51) as a minimum essential promotoractivity from pTKβ having TK promotor (Chrontech Inc., catalogue No.6179-1). In the upper stream of TK promotor, four times repeated UASsequence was inserted, which is the response element of Gal4 protein, abasic transcription factor in yeast, to construct 4×UAS-TK-Luc. asreporter gene. The following is the enhancer sequence used (Sequence No.1).

[0150] Sequence No. 1: Enhancer sequence repeating Gal4 response elementfour-times tande mly.

[0151] 5′-T(CGACGGAGTACTGTCCTCCG)×4 AGCT-3′

[0152] A vector was prepared as described hereafter which expresseschimeric receptor protein wherein in carboxy terminus of yeast Gal4protein DNA binding domain was fused to ligand binding domain of humanPPARα or γ. That is to say, PicaGene Basic Vector 2 (trade name, ToyoInk Inc., catalogue No. 309-04821) was used as a basic expressionvector, the structural gene was exchanged for that of chimeric receptorprotein, while promotor and enhancer domains were kept as they were.

[0153] DNA encoding a fused protein composed of Gal4 DNA binding domain,the 1st to 147th amino acid sequence linked to the ligand binding domainof human PPARα or γ in frame was inserted to the downstream ofpromotor/enhancer in PicaGene Basic Vector 2 (trade name, Toyo Ink Inc.,catalogue No. 309-04821). Here the DNA was aligned as follows; in theamino terminus of human PPARα or γ ligand binding domain, nucleartranslocation signal originated from SV-40 T-antigen, Ala Pro Lys LysLys Arg Lys Val Gly (sequence No. 2) was added to make fusion proteinlocalizing intranuclearly. On the other hand, in the carboxy terminus ofthem, influenza hemagglutinin epitope, Tyr Pro Tyr Asp Val Pro Asp TyrAla (sequence No. 3) and stop codon for translation was added in thisorder, to detect an expressed fused protein tagged epitope sequence.

[0154] According to the comparison of human PPAR structures described inthe literatures by R. Mukherjee at al. (See J. Steroid Biochem. Molec.Biol., 51, 157 (1994)), M. E. Green et al., (See Gene Expression., 4,281 (1995)), A. Elbrecht et al. (See Biochem Biophys. Res. Commun., 224,431 (1996)) or A. Schmidt et al. (See Mol. Endocrinology., 6, 1634(1992)), the portion of structural gene used as ligand binding domain ofhuman PPARα or γ was DNA encoding the following peptide:

[0155] human PPARα ligand binding domain: Ser¹⁶⁷-Tyr⁴⁶⁸

[0156] human PPARγ ligand binding domain: Ser¹⁷⁶-Tyr⁴⁷⁸

[0157] (each human PPARγ1 ligand binding domain and human PPARγ2 ligandbinding domain is Ser²⁰⁴-Tyr⁵⁰⁶which is identical sequence each other).

[0158] In order to measure basal level of transcription, an expressionvector containing DNA binding domain of Gal4 protein lacking in PPARligand binding domain, which is exclusively encoding the 1st to 147thamino acid sequence in Gal4 protein was also prepared.

[0159] (2) Luciferase Assay Using Human PPARα or γ

[0160] CV-1 cells used as host cells were cultured by a conventionaltechnique. That is to say, Dulbecco's modified Eagle medium (DMEM)supplemented 10% bovine fetal serum (GIBCO BRL Inc., catalogue No.26140-061) and 50 U/ml of penicillin G and 50 μg/ml of streptomycinsulfate were used to culture CV-1 cells under the atmosphere of 5%carbon dioxide gas at 37° C.

[0161] 2×10⁶ cells were seeded in a 10 cm dish, and once washed with themedium without serum, followed by addition of the medium (10 ml)thereto. Reporter gene (10 μg), Gal4-PPAR expression vector (0.5 μg) and50 μl of LipofectAMINE (GIBRO BRL Inc., catalogue No. 18324-012) werewell mixed and added to the culture to introduce these DNAs into thehost cells. They were cultured at 37° C. for 5˜6 hours, and thereto wasadded 10 ml of medium containing 20% of dialyzed bovine fetal serum(GIBRO BRL Inc., catalogue No. 26300-061), and then cultured at 37° C.overnight. The cells were dispersed by trypsin, and they were againseeded in 96-well plates in a density of 8000 cells/100 ml of DMEM-10%dialyzed serum/well. Several hours after the cultivation, when cellswere attached to the plastic ware, then 100 μl of DMEM-10% dialyzedserum containing the compounds of the present invention, whoseconcentration is twice as high as the final concentration of them, wasadded thereto. The culture was settled at 37° C. for 42 hours and thecells were dissolved to measure luciferase activity according tomanufacturer's instruction.

[0162] As to PPARα agonistic activity, the relative activity of thecompounds of the present invention (10 μM) was shown in Table 25, underthe condition that luciferase activity was defined as 1.0 in case ofcarbacyclin (10 μM) as a positive control compound, which could activatetranscription of luciferase gene significantly to PPAR α (See Eur. J.Biochem., 233, 242 (1996); Genes & Development., 10, 974 (1996)).

[0163] As to PPARγ agonistic activity, the relative activity of thecompounds of the present invention (10 μM) was shown in Table 26, underthe condition that luciferase activity was defined as 1.0 in case oftroglitazone (10 μM) as a positive control compound, which couldactivate transcription of luciferase gene significantly to PPARγ (SeeCell., 83, 863 (1995); Endocrinology., 137, 4189 (1996) and J. Med.Chem., 39, 665 (1996)) and has been already launched as hypoglycemicagent.

[0164] Furthermore, assay of each compound was carried out three timesto examine its reproducibility and to confirm the dose dependentactivity. TABLE 25 Relative Activity to a positive control compoundExample Nos. (carbacyclin = 1) Example 3 2.6 Example 3(1) 1.5 Example3(2) 3.1 Example 3(3) 1.8

[0165] TABLE 26 Relative Activity to a positive control compound ExampleNos. (troglitazone = 1) Example 3 2.3 Example 3(1) 1.1 Example 3(2) 2.3Example 3(3) 2.2

[0166] Hypoglycemic and Hypolipidemic Effects

[0167] Male, 7-weeks old KKAy/Ta mice weighed from 35 to 40 g (five miceper group) were pre-breaded for approximately one week and acclimatizedfor three days on milled diet. On the first day of the experiment (Day0), mice were divided into some groups according to weight, plasmaglucose and triglyceride (TG) levels to minimize the differences amonggroups. From the next day for two days they were given compounds by foodmixture containing 0.03% (w/w) of the compound of the present inventionor by milled diet only. At 13:00 of the third day, blood samples werecollected to measure glucose and TG levels. The results are shown inTable 27. Additionally, there was no significant difference in the foodintake between control group (milled diet only) and compounds-treatedgroup (milled diet containing 0.03% compounds). TABLE 27 blood sugar TGlevel level (mg/dl) (mg/dl) Example Nos. 4 days 4 days Control 520 ± 147439 ± 234 Example 3 260 ± 37*  43 ± 12* 46 mg/kg/day by food mixture(conversion value) Example 3(1) 253 ± 27*  44 ± 11* 43 mg/kg/day by foodmixture (conversion value) Example 3(2) 243 ± 37*  45 ± 12* 44 mg/kg/dayby food mixture (conversion value) Example 3(3) 234 ± 31*  31 ± 15* 47mg/kg/day by food mixture (conversion value)

[0168] Hypocholesterolemic and Hypolipidemic Effects

[0169] Male, six-weeks old SD rats (five rats per group) were left totake milled diet and water ad libitum and were acclimatized for 1 week.

[0170] At 9:00 on the first day of the experiment (Day 0), bloodsampling was done from tail vein. The rats were divided into some groupsaccording to body weight, triglyceride (TG), non-esterified fatty acid(NEFA) and total cholesterol (TC) levels to minimize differences of theparameters among the groups. At 17:00 of the day, the compound of thepresent invention dissolved in 0.5% aqueous solution ofcarboxymethylcellulose (CMC) was orally administered, and thereafter,with hypercholesterolemic food (5.5% peanut oil, 1.5% cholesterol and0.5% cholic acid were mixed with milled CRF-1 diet, Charles River Inc.)was given to the rats.

[0171] At 9:00 of the next day, blood sampling was done from tail vein.The lipid levels in blood (TG, NEFA and TC levels) after administrationof the compounds of the present invention were measured. The results areshown in Table 28. There was no significant difference of the foodintake between the control group (provided only 0.5% CMC) and the grouptreated with the compounds of the present invention. TABLE 28 IC levelIG level NEFA level Example Nos. (mg/dl) (mg/dl) (mEq/l) Control 167 ±13 163 ± 18 615 ± 80 Example 3  87 ± 5*  73 ± 7* 207 ± 25* Example 3(1)107 ± 4*  92 ± 26 394 ± 49* Exmaple 3(2)  86 ± 6*  62 ± 7* 145 ± 18*Example 3(3)  91 ± 4*  79 ± 12* 213 ± 31*

[0172] The hypoglycemic or hypolipidemic effects observed in KKAy miceimply the possibility of preventives and/or remedies for diabetes andhyperlipidemia etc. Cholesterol-lowering and free fatty acid-loweringeffects observed in high cholesterol diet-fed rats imply that thecompounds of the present invention are useful as preventives and/orremedies of atherosclerosis etc.

[0173] The compounds of the present invention possess the hypoglycemicor hypolipidemic (TG, NEFA) effects as well as cholesterol-loweringeffect, so they are expected to be more useful to compare with themarketed hypoglycemic or hypolipidemic drugs.

[0174] In addition, it has been known that hyperlipidemia, obesity ordiabetes are one of cause of uncondition in liver function andhyperlipid in liver. Therefore, the compounds of the present inventionare expected to be the drugs to improve liver function which has notbeen marketed.

[0175] Industrial Applicability

[0176] [Effect]

[0177] The compound of formula (I) of the present invention, non-toxicsalts thereof, acid addition salts thereof and hydrates thereof havePPAR regulating effect, and therefore are expected to be applied ashypoglycemic agents, hypolipidemic agents, preventives and/or remediesfor diseases associated with metabolic disorders (diabetes, obesity,syndrome X, hypercholesterolemia and hyperlipoproteinemia etc.),hyperlipidemia, atherosclerosis, hypertension, circulatory diseases,overeating, coronary heart diseases etc., HDL cholesterol-elevatingagents, LDL cholesterol and/or VLDL cholesterol-lowering agents andagents for relieving risk factors of diabetes or syndrome X.

[0178] The compound of formula (I) of the present invention, non-toxicsalts thereof, acid addition salts thereof and hydrates thereof haveparticularly PPARα agonist and/or PPARγ agonist effect, and thereforeare thought to be useful as hypoglycemic agents, hypolipidemic agents,preventives and/or remedies for diseases associated with metabolicdisorders (diabetes, obesity, syndrome X, hypercholesterolemia,hyperlipoproteinemia etc.), hyperlipidemia, atherosclerosis,hypertension, circulatory diseases and overeating etc. Since they areexpected to have HDL cholesterol-elevating effect, LDL cholesteroland/or VLDL cholesterol-lowering effect, inhibition of progress ofatherosclerosis and its treatment, and inhibitory effect againstobesity, they are also expected to be useful for the treatment and/orprevention of diabetes as hypoglycemic agents, for the amelioration ofhypertension, for the relief from risk factors of syndrome X, and aspreventives against occurrence of coronary heart diseases.

[0179] [Toxicity]

[0180] The toxicity of the compound of the present invention is very lowand therefore, it may be considered that the compounds of the presentinvention are safe for pharmaceutical use.

[0181] [Application for Pharmaceuticals]

[0182] For the purpose above described, the compounds of the presentinvention of the formula (I), non-toxic salts and acid addition saltsthereof and hydrates thereof may be normally administered systemicallyor locally, usually by oral or parenteral administration.

[0183] The doses to be administered are determined depending upon age,body weight, symptom, the desired therapeutic effect, the route ofadministration, and the duration of the treatment etc. In the humanadult, the doses per person per dose are generally between 1 mg and 1000mg, by oral administration, up to several times per day, and between 0.1mg and 100 mg, by parenteral administration (preferred into vein) up toseveral times per day, or continuous administration between 1 and 24hrs. per day into vein.

[0184] As mentioned above, the doses to be used depend upon variousconditions. Therefore, there are cases in which doses lower than orgreater than the ranges specified above may be used.

[0185] The compounds of the present invention may be administered asinner solid compositions or inner liquid compositions for oraladministration, or as injections, liniments or suppositories etc. forparenteral administration.

[0186] Inner solid compositions for oral administration includecompressed tablets, pills, capsules, dispersible powders and granulesetc. Capsules contain hard capsules and soft capsules.

[0187] In such inner solid compositions, one or more of the activecompound(s) is or are, admixed with at least one inert diluent (lactose,mannitol, glucose, microcrystalline cellulose, starch etc.), connectingagents (hydroxypropyl cellulose, polyvinylpyrrolidone, magnesiummetasilicate aluminate etc.), disintegrating agents (cellulose calciumglycolate etc.), lubricating agents (magnesium stearate etc.),stabilizing agents, assisting agents for dissolving (glutamic acid,asparaginic acid etc.) etc. to prepare pharmaceuticals by known methods.The pharmaceuticals may, if desired, be coated with material such assugar, gelatin, hydroxypropyl cellulose or hydroxypropyl cellulosephthalate etc., or be coated with two or more films. And further,coating may include containment within capsules of absorbable materialssuch as gelatin.

[0188] Inner liquid compositions for oral administration includepharmaceutically-acceptable water-agents, suspensions, emulsions, syrupsand elixirs etc. In such liquid compositions, one or more of the activecompound(s) is or are comprised in inert diluent(s) commonly used in theart (purified water, ethanol or mixture thereof etc.). Besides inertdiluents, such compositions may also comprise adjuvants such as wettingagents, suspending agents, emulsifying agents, sweetening agents,flavouring agents, perfuming agents, preserving agents and buffer agentsetc.

[0189] Injections for parenteral administration include solutions,suspensions and emulsions and solid injections which are dissolved orsuspended in solvent when it is used. One or more active compound(s) isor are dissolved, suspended or emulsified in a solvent when suchcompositions are used. Aqueous solutions or suspensions includedistilled water for injection and physiological salt solution, plantoil, propylene glycol, polyethylene glycol and alcohol such as ethanoletc., and mixture thereof. Such compositions may comprise additionaldiluents such as stabilizing agent, assisting agents for dissolving(glutamic acid, asparaginic acid, POLYSOLBATE80 (registered trade mark)etc.), suspending agents, emulsifying agents, dispersing agents, bufferagents, preserving agents etc. They may be sterilized for example, byfiltration through a bacteria-retaining filter, by incorporation ofsterilizing agents in the compositions or by irradiation. They may alsobe manufactured in the form of sterile solid compositions and which canbe dissolved in sterile water or some other sterile diluent forinjection immediately before use.

[0190] Other compositions for parenteral administration include liquidsfor external use, ointments, endermic liniments, aerosols, spraycompositions, suppositories and pessaries for vaginal administrationetc. which comprise one or more of the active compound(s) and may beprepared by known methods.

[0191] Spray compositions may comprise additional substances other thaninert diluents: e.g. stabilizing agents such as sodium hydrogen sulfate,stabilizing agents to give isotonicity, isotonic buffer such as sodiumchloride, sodium citrate, citric acid. For preparation of such spraycompositions, for example, the method described in the U.S. Pat. Nos.2,868,691 or 3,095,355 may be used.

BEST MODE FOR CARRYING OUT THE INVENTION

[0192] The following Reference Examples and Examples illustrate thepresent invention, but do not limit the present invention.

[0193] The solvents in the parentheses show the developing or elutingsolvents and the ratios of the solvents used are by volume inchromatographic separations and TLC.

[0194] Solvents in the parentheses of NMR show the solvents use formeasurement.

REFERENCE EXAMPLE 1

[0195] 5-methyl-2-phenyloxazol-4-ylcarboxylic acid.methyl ester

[0196] Benzaldehyde (11 ml) and hydroxyiminoacetoacetic acid.methylester (18.8 g) were dissolved into acetic acid (35 ml) and the resultantsolution was saturated by hydrochloric acid under cooling with ice, andwas stirred for 2 hours. The reaction mixture was diluted with ether,and the precipitate was filtered out. The precipitate was suspended inacetic acid (200 ml), and a zinc powder (20 g) was added thereto undercooling with ice. The reaction (mixture was stirred for 30 minutes onwater bath. The reaction mixture was filtered off in order to exclude azinc powder. A purified water was add to the filtrate, and theprecipitate was filtered out. The precipitate was washed with a purifiedwater, and dried over to give the title compound (11.7 g) having thefollowing physical data.

[0197] TLC: Rf 0.44 (hexane:ethyl acetate=4:1);

[0198] NMR (CDCl₃): δ8.14−8.02 (m, 2H), 7.51−7.42 (m, 3H), 3.95 (s, 3H),2.72 (s, 3H).

REFERENCE EXAMPLE 2

[0199] (5-methyl-2-phenyloxazol-4-yl)methanol

[0200] Lithium aluminum hydride (3.07 g) was suspended in anhydroustetrahydrofuran (40 ml), and a solution of the compound prepared inReference Example 1 (11.7 g) in anhydrous tetrahydrofuran (40 ml) wasadded dropwise thereto under cooling with ice. The reaction mixture wasstirred for 15 minutes. A saturated aqueous solution of sodium sulfate(10 ml) was added dropwise to the reaction mixture slowly, and thereaction mixture was filtered off. The filtrate was concentrated to givethe title compound (7.92 g) having the following physical data.

[0201] TLC: Rf 0.19 (hexane:ethyl acetate=2:1);

[0202] NMR (CDCl₃): δ8.04−7.93 (m, 2H), 7.48−7.38 (m, 3H), 4.60 (s, 2H),2.40 (s, 3H).

REFERENCE EXAMPLE 3

[0203] 5-methyl-2-phenyloxazol-4-ylmethyl bromide

[0204] Triphenylphosphine (8.32 g) and carbon tetrabromide (10.5 g) wereadded to a solution of the compound prepared in Reference Example 2 (4.0g) in dichloromethane (210 ml), and the resultant solution was stirredfor 4 hours at room temperature. The reaction mixture was concentrated.The residue was purified by silica gel column chromatography(hexane:ethyl acetate=8:1) to give the title compound (4.93 g) havingthe following physical data.

[0205] TLC: Rf 0.66 (hexane:ethyl acetate=4:1);

[0206] NMR (CDCl₃): δ8.06−7.94 (m, 2H), 7.48−7.38 (m, 3H), 4.45 (s, 2H),2.41 (s, 3H).

REFERENCE EXAMPLE 4

[0207] 2-formyl-5-(5-methyl-2-phenyloxazol-4-ylmethyl)furan

[0208] Under an atmosphere of argon gas,tetrakis(triphenylphosphine)-palladium (1.13 g) was add to a solution ofthe compound prepared in Reference Example 3 (4.93 g) and5-n-butylstannyl-2-furaldehyde (9.0 g) in dimethylformamide (100 ml),and the resultant solution was stirred for 1 hour at 70° C. Ice waterwas added to the reaction mixture, and it was extracted with ethylacetate. The extract was washed with a 10% aqueous solution of ammoniaand a saturated aqueous solution of sodium chloride, successively, driedover anhydrous magnesium sulfate and concentrated. The residue waspurified by silica gel column chromatography (hexane:ethyl acetate=4:1)to give the title compound (3.38 g) having the following physical data.

[0209] TLC: Rf 0.39 (hexane:ethyl acetate=2:1);

[0210] NMR (CDCl₃): δ9.55 (s, 1H), 8.04−7.92 (m, 2H), 7.48−7.38 (m, 3H),7.18 (d, J=3.6 Hz,1H), 6.35 (d, J=3.6 Hz,1H), 3.99 (s, 2H), 2.36 (s,3H).

REFERENCE EXAMPLE 5

[0211](2E)-3-(5-(5-methyl-2-phenyloxazol-4-ylmethyl)furan-2-yl)-2-propenoicacid. ethyl ester

[0212] Under cooling with ice, diethylphosphonoacetic acid.ethyl ester((2.97 ml) was added dropwise to a suspension of sodium hydride (610 mg)in tetrahydrofuran (60 ml) under an atmosphere of argon gas, and theresultant solution was stirred for 1 hour at room temperature. Ice waterwas added to the reaction mixture, and it was extracted with ethylacetate. The extract was washed with a purified water and a saturatedaqueous solution of sodium chloride, successively, dried over anhydrousmagnesium sulfate and concentrated. The residue was purified by silicagel column chromatography (hexane:ethyl acetate=4:1) to give the titlecompound (4.03 g) having the following physical data.

[0213] TLC: Rf 0.65 (hexane:ethyl acetate=2:1);

[0214] NMR (CDCl₃): δ8.04−7.93 (m, 2H), 7.48−7.32 (m, 4H), 6.53 (d,J=3.0 Hz, 1H), 6.29−6.16 (m, 2H), 4.23 (q, J=7.0 Hz, 2H), 3.92 (s, 2H),2.34 (s, 3H), 1.31 (t, J=7.0 Hz, 3H).

REFERENCE EXAMPLE 6

[0215] (2E)-3-(5-(5-methyl-2-phenyloxazol-4-yl methyl)furan-2-yl)-2-propenol

[0216] A solution of the compound prepared in Reference Example 5 (3.03g) in anhydrous tetrahydrofuran (90 ml) was cooled to −78° C., and underan atmosphere of argon gas, diisobutylaluminum hydride (0.94 M hexanesolution, 33 ml) was added thereto gradually. After confirmation ofreaction completion, a saturated aqueous solution of sodium sulfate (5ml) was added dropwise to the reaction mixture slowly, and it was warmedto room temperature. The deposited insoluble material was filtered out.The filtrate was concentrated to give the tittle compound (2.65 g)having the following physical data.

[0217] TLC: Rf 0.31 (hexane:ethyl acetate=2:1);

[0218] NMR (CDCl₃): δ8.04−7.92 (m, 2H), 7.48−7.36 (m, 3H), 6.39 (d,J=16.0 Hz, 1H), 6.22 (dt, J=16.0, 5.0 Hz, 1H), 6.15 (d, J=3.0 Hz, 1H),6.07 (d, J=3.0 Hz,1H), 4.28 (t, J=5.0 Hz, 2H), 3.90 (s, 2H), 2.31 (s,3H).

EXAMPLE 1

[0219] 2-((2E)-3-(5-(5-methyl-2-phenyloxazol-4-ylmethyl)furan-2-yl)-2-propenylthio)acetic acid.methyl ester

[0220] A solution of the compound prepared in Reference Example 6 (2.64g) in dichloromethane (45 ml) was cooled to −50° C., and triethylamine(1.89 ml) and methanesulfonyl chloride (0.83 ml) were added thereto, andthe resultant solution was stirred for 15 minutes. Diisopropylethylamine(7.8 ml) and thioglycolic acid.methyl ester (3.24 ml) were added to thereaction mixture, and it was stirred for 1 hour at −20° C. Ice water wasadded to the reaction mixture, and it was extracted with ethyl acetate.The extract was washed with a purified water and a saturated aqueoussolution of sodium chloride, successively, dried over and concentrated.The residue was purified by silica gel column chromatography(hexane:ethyl acetate=9 :1) to give the title compound (4.03 g) havingthe following physical data.

[0221] TLC: Rf 0.36 (hexane:ethyl acetate=4:1);

[0222] NMR (CDCl₃): δ8.03−7.94 (m, 2H), 7.48−7.38 (m, 3H), 6.27 (d,J=15.6 Hz, 1H), 6.15 (d, J=3.0 Hz, 1H), 6.08 (d, J=3.0 Hz, 1H),6.10−5.90 (m, 1H), 3.89 (s, 2H), 3.71 (s, 3H), 3.37 (d, J=7.0 Hz, 2H),3.19 (s, 2H), 2.32 (s,

EXAMPLE 2˜EXAMPLE 2(11)

[0223] The following compounds were obtained by the same procedure as aseries of reactions of Reference Example 1→Reference Example 2→ReferenceExample 3→Reference Example 4→Reference Example 5→Reference Example6→Example 1.

[0224] Also, The following compounds were used as starting compoundswhen the same procedure as Reference Example 1 was done.

[0225] Example 2: 4-methylbenzaldehyde

[0226] Example 2(1), Example 2(4) and Example 2(5): 3,4-(methylenedioxy)benzaldehyde

[0227] Example 2(2): 4-ethylbenzaldehyde

[0228] Example 2(3): benzaldehyde

[0229] Example 2(6), 2(8), 2(9): 4-dimethylaminobenzaldehyde

[0230] Example 2(7), 2(10), 2(11):2-dimethylamino-5-pyridinecarbaldehyde

[0231] Also, in the case of Example 2(3),5-n-butylstannyl-2-thienylaldehyde was used instead of5-n-butylstannyl-2-furaldehyde in Reference Example 4.

[0232] Also, in the case of Example 2(4), Example 2(8) and Example2(10), 2-mercapto-2-methylpropanoic acid.ethyl ester was used instead ofthioglycolic acid.methyl ester in Example 1.

[0233] In the case of Example 2(5), Example 2(9) and Example 2(11),(1-mercapto)cyclobutanecarboxylic acid.ethyl ester was used instead ofthioglycolic acid.methyl ester in Example 1.

EXAMPLE 2

[0234]2-((2E)-3-(5-(5-methyl-2-(4-methylphenyl)oxazol-4-ylmethyl)furan-2-yl)-2-propenylthio)aceticacid.methyl ester

[0235] TLC: Rf 0.59 (hexane:ethyl acetate=2:1);

[0236] NMR (CDCl₃): δ7.87 (d, J=8.0 Hz, 2H), 7.23 (d, J=8.0 Hz, 2H),6.27 (d, J=15.8 Hz, 1H), 6.14 (d, J=3.2 Hz, 1H), 6.07 (d, J=3.2 Hz, 1H),5.99 (dt, J=15.8, 7.6 Hz, 1H), 3.88 (s, 2H), 3.71 (s, 3H), 3.37 (d,J=7.6 Hz, 2H), 3.19 (s, 2H), 2.38 (s, 3H), 2.31 (s, 3H).

EXAMPLE 2(1)

[0237]2-((2E)-3-(5-(5-methyl-2-(1,3-dioxaindan-5-yl)oxazol-4-ylmethyl)furan-2-yl)-2-propenylthio)aceticacid.methyl ester

[0238] TLC: Rf 0.35 (hexane:ethyl acetate=4:1);

[0239] NMR (CDCl₃): δ7.53 (dd, J=8.0, 1.5 Hz, 1H), 7.44 (d, J=1.5 Hz,1H), 6.85 (d, J=8.0 Hz, 1H), 6.27 (d, J=16.0 Hz, 1H), 6.14 (d, J=3.0 Hz,1H), 6.09-5.90 (m, 4H), 3.86 (s, 2H), 3.71 (s, 3H), 3.37 (d, J=7.5 Hz,2H), 3.19 (s, 2H), 2.30 (s, 3H).

EXAMPLE 2(2)

[0240]2-((2E)-3-(5-(5-methyl-2-(4-ethylphenyl)oxazol-4-ylmethyl)furan-2-yl)-2-propenylthio)aceticacid.methyl ester

[0241] TLC: Rf 0.52 (hexane:ethyl acetate=3:1);

[0242] NMR (CDCl₃): δ7.90 (d, J=8.3 Hz, 2H), 7.25 (d, J 8.3 Hz, 2H),6.27 (d, J=15.8 Hz, 1H), 6.14 (d, J=3.2 Hz, 1H), 6.06 (d, J=3.2 Hz, 1H),5.99 (dt, J=15.8, 7.8 Hz, 1H), 3.88 (s, 2H), 3.71 (s, 3H), 3.37 (d,J=7.8 Hz, 2H), 3.19 (s, 2H), 2.68 (q, J=7.6 Hz, 2H), 2.31 (s, 3H), 1.25(t, J=7.6 Hz, 3H).

EXAMPLE 2(3)

[0243]2-((2E)-3-(5-(5-methyl-2-phenyloxazol-4-ylmethyl)thiophen-2-yl)-2-propenylthio)aceticacid.methyl ester

[0244] TLC: Rf 0.48 (ethyl acetate:hexane=1:3);

[0245] NMR (CDCl₃): δ8.01−7.97 (m, 2H), 7.45−7.38 (m, 3H), 6.77−6.73 (m,2H), 6.54 (br.d, J=15.4 Hz,1H), 5.85 (dt, J=15.4, 7.6 Hz,1H), 4.00 (s,2H), 3.70 (s, 3H), 3.34 (br.d, J=7.6 Hz, 2H), 3.17 (s, 2H), 2.33 (s,3H).

EXAMPLE 2(4)

[0246]2-methyl-2-((2E)-3-(5-(5-methyl-2-(1,3-dioxaindan-5-yl)oxazol-4-ylmethyl)furan-2-yl)-2-propenylthio)propanoicacid.ethyl ester

[0247] TLC: Rf 0.38 (ethyl acetate:hexane=1:3);

[0248] NMR (CDCl₃): δ7.52 (dd, J=8.0, 2.0 Hz, 1H), 7.44 (d, J=2.0 Hz,1H), 6.84 (d, J=8.0 Hz, 1H), 6.27 (d, J=15.5 Hz, 1H), 6.09 (d, J=3.0 Hz,1H), 6.04 (d, J=3.0 Hz, 1H), 6.03 (dt, J=15.5, 7.5 Hz, 1H), 6.01 (s,2H), 4.13 (q, J=7.0 Hz, 2H), 3.84 (s, 2H), 3.40 (d, J=7.5 Hz, 2H), 2.27(s, 3H), 1.53 (s, 6H), 1.26 (t, J=7.0 Hz, 3H).

EXAMPLE 2(5)

[0249]1-((2E)-3-(5-(5-methyl-2-(1,3-dioxaindan-5-yl)oxazol-4-ylmethyl)furan-2-yl)-2-propenylthio)cyclobutanecarboxylicacid.ethyl ester

[0250] TLC: Rf 0.33 (ethyl acetate:hexane=1:3);

[0251] NMR (CDCl₃): δ7.53 (dd, J=8.0, 2.0 Hz, 1H), 7.44 (d, J=2.0 Hz,1H), 6.85 (d, J=8.0 Hz, 1H), 6.26 (d, J=15.5 Hz, 1H), 6.10 (d, J=1.5 Hz,1H), 6.05 (dt, J=15.5, 7.0 Hz, 1H), 6.04 (d, J=1.5 Hz, 1H), 6.01 (s,2H), 4.15 (q, J=7.0 Hz, 2H), 3.85 (s, 2H), 3.33 (d, J=7.0 Hz, 2H), 2.64(m, 2H), 2.28 (s, 3H), 2.40−2.05 (m, 3H), 1.89 (m,1H), 1.26 (t, J=7.0Hz, 3H).

EXAMPLE 2(6)

[0252] 2-((2E)-3-(5-(5-methyl-2-(4-dimethylaminophenyl)oxazol-4-ylmethyl)furan-2-yl)-2-propenylthio)acetic acid.methyl ester

[0253] TLC: Rf 0.46 (hexane:ethyl acetate=2:1);

[0254] NMR (CDCl₃): δ7.84 (m, 2H), 6.70 (m, 2H), 6.26 (d, J=15.6 Hz,1H), 6.14 (d, J=3.2 Hz, 1H), 6.06 (d, J=3.2 Hz, 1H), 5.99 (dt, J=15.6,7.2 Hz, 1H), 3.86 (s, 2H), 3.70 (s, 3H), 3.37 (d, J=7.2 Hz, 2H), 3.19(s, 2H), 3.01 (s, 6H), 2.28 (s, 3H).

EXAMPLE 2(7)

[0255] 2-((2E)-3-(5-(5-methyl-2-(2-dimethylaminopyridin-5-yl)oxazol-4-ylmethyl)furan-2-yl)-2-propenylthio) acetic acid.methyl ester

[0256] TLC: Rf 0.38 (hexane:ethyl acetate=1:1);

[0257] NMR (CDCl₃): δ8.74 (dd, J=2.4, 0.8 Hz, 1H), 8.00 (dd, J=9.0, 2.4Hz, 1H), 6.52 (dd, J=9.0, 0.8 Hz, 1H), 6.27 (d, J=15.6 Hz, 1H), 6.14 (d,J=3.0 Hz, 1H), 6.07 (d, J=3.0 Hz,1H), 5.97 (d, J=15.6, 8.0 Hz, 1H), 3.86(s, 2H), 3.71 (s, 3H), 3.37 (dd, J=8.0, 0.8 Hz, 2H), 3.19 (s, 2H), 3.15(s, 6H), 2.29 (s, 3H).

EXAMPLE 2(8)

[0258]2-methyl-2-((2E)-3-(5-(5-methyl-2-(4-dimethylaminophenyl)oxazol-4-ylmethyl)furan-2-yl)-2-propenylthio)propanoicacid.ethyl ester

[0259] TLC: Rf 0.57 (hexane:ethyl acetate=2:1);

[0260] NMR (CDCl₃): δ7.84 (m, 2H), 6.71 (m, 2H), 6.27 (d, J=15.8 Hz,1H), 6.09 (d, J=3.4 Hz, 1H), 6.04 (d, J=3.4 Hz, 1H), 6.03 (m, 1H), 4.13(q, J=7.2 Hz, 2H), 3.85 (s, 2H), 3.40 (d, J=7.2 Hz, 2H), 3.01 (s, 6H),2.26 (s, 3H), 1.53 (s, 6H), 1.25 (t, J=7.2 Hz, 3H).

EXAMPLE 2(9)

[0261]1-((2E)-3-(5-(5-methyl-2-(4-dimethylaminopheny)oxazol-4-ylmethyl)furan-2-yl)-2-propenylthio)cyclobutanecarboxylicacid.ethyl ester

[0262] TLC: Rf 0.53 (hexane:ethyl acetate=2:1);

[0263] NMR (CDCl₃): δ7.84 (m, 2H), 6.71 (m, 2H), 6.26 (d, J 15.8 Hz,1H), 6.09 (d, J=3.2 Hz, 1H), 6.05 (m, 1H), 6.04 (d, J=3.2 Hz, 1H), 4.15(q, J=7.2 Hz 2H), 3.85 (s, 2H), 3.33 (d, J=7.0 Hz, 2H), 3.01 (s, 6H),2.72-2.56 (m, 2H), 2.28−2.10 (m, 3H), 2.26 (s, 3H), 1.90 (m, 1H), 1.26(t, J=7.2 Hz, 3H).

EXAMPLE 2 (10)

[0264] 2-methyl-2-((2E)-3-(5-(5-methyl-2-(4-dimethylaminopyridin-5-yl)oxazol-4-ylmethyl)furan-2-yl)-2-propenylthio)propanoic acid.ethyl ester

[0265] TLC: Rf 0.47 (hexane:ethyl acetate=1:1);

[0266] NMR (CDCl₃): δ8.74 (dd, J=2.4, 0.8 Hz, 1H), 8.00 (dd, J=9.0, 2.4Hz, 1H), 6.52 (dd, J=9.0, 0.8 Hz, 1H), 6.27 (d, J 15.6 Hz, 1H), 6.10 (d,J=3.2 Hz, 1H), 6.05 (d, J=3.2 Hz, 1H), 6.01 (d, J=15.6, 7.0 Hz, 1H),4.13 (q, J=7.2 Hz, 2H), 3.84 (s, 2H), 3.41 (dd, J=7.0, 0.8 Hz, 2H), 3.14(s, 6H), 2.27 (s, 3H), 1.53 (s, 6H), 1.26 (t, J=7.2 Hz, 3H).

EXAMPLE 2(11)

[0267]1-((2E)-3-(5-(5-methyl-2-(4-dimethylaminopyridin-5-yl)oxazol-4-ylmethyl)furan-2-yl)-2-propenylthio)cyclobutanecarboxylicacid.ethyl ester

[0268] TLC: Rf 0.53 (hexane:ethyl acetate=1:1);

[0269] NMR (CDCl₃): δ8.73 (dd, J=2.4, 0.8 Hz, 1H), 8.00 (dd, J=9.0, 2.4Hz, 1H), 6.52 (dd, J=9.0, 0.8 Hz, 1H), 6.20 (d, J 15.8 Hz, 1H), 6.10 (d,J=3.0 Hz, 1H), 6.05 (d, J=3.0 Hz, 1H), 6.03 (d, J=15.8, 7.0 Hz, 1H),4.16 (q, J=7.2 Hz, 2H), 3.84 (s, 2H), 3.33 (dd, J=7.0, 0.8 Hz, 2H), 3.14(s, 6H), 2.70−2.53 (m, 2H), 2.36−2.04 (m, 6H), 1.96−1.70 (m,1 H), 1.26(t, J=7.2 Hz, 3H).

EXAMPLE 3

[0270]2-((2E)-3-(5-(5-methyl-2-phenyloxazol-4-ylmethyl)furan-2-yl)-2-propenylthio)aceticacid

[0271] 2N aqueous solution of sodium hydroxide (7.4 ml) was added to asolution of the compound prepared in Example 1 (1.88 g) in methanol (49ml), and the resultant solution was stirred for 5 hours at roomtemperature. 2N hydrochloric acid (7.4 ml) was added to the reactionmixture, and the resultant solution was concentrated. The residue wascrystallized from ethyl acetate to give the title compound (1.28 g)having the following physical data.

[0272] TLC: Rf 0.73 (chloroform:methanol=5:1);

[0273] NMR (CDCl₃): δ7.96-8.01 (m, 2H), 7.39-7.46 (m, 3H), 6.26 (d,J=15.6 Hz, 1H), 6.14 (d, J=3.2 Hz, 1H), 6.06 (d, J=3.2 Hz, 1H), 6.01(dt, J=15.6, 7.6 Hz,1H), 3.90 (s, 2H), 3.38 (d, J=7.6 Hz, 2H), 3.21 (s,2H), 2.33 (s, 3H).

EXAMPLE 3(1)˜EXAMPLE 3(12)

[0274] The following compounds were obtained by the same procedure asExample 3, using compounds prepared in Example 2˜Example 2(5).

EXAMPLE 3(1)

[0275]2-((2E)-3-(5-(5-methyl-2-(4-methylphenyl)oxazol-4-ylmethyl)furan-2-yl)-2-propenylthio)aceticacid

[0276] TLC: Rf 0.40 (chloroform:methanol=10:1);

[0277] NMR (CDCl₃): δ7.87 (d, J=8.0 Hz, 2H), 7.23 (d, J=8.0 Hz, 2H),6.25 (d, J=15.6 Hz, 1H), 6.13 (d, J=3.2 Hz, 1H), 6.05 (d, J=3.2 Hz, 1H),6.00 (dt, J=15.6, 7.2 Hz, 1H), 3.89 (s, 2H), 3.37 (d, J=7.2 Hz, 2H),3.20 ( s, 2H), 2.38 (s, 3H), 2.31 (s, 3H).

EXAMPLE 3(2)

[0278] 2-((2E) -3-(5-(5-methyl-2-(1,3-dioxaindan-5-yl)oxazol-4-ylmethyl)furan-2-yl)-2-propenylthio)acetic acid

[0279] TLC: Rf 0.53 (chloroform:methanol=10:1);

[0280] NMR (CDCl₃): δ7.53 (dd, J=8.0, 1.6 Hz, 1 H), 7.44 (d, J=1.6 Hz,1H), 6.85 (d, J=8.0 Hz, 1H), 6.25 (d, J=15.5 Hz, 1H), 6.14 (d, J=3.0 Hz,1H), 6.09-5.92 (m, 4H), 3.87 (s, 2H), 3.38 (d, J=7.5 Hz, 2H), 3.20 (s,2H), 2.30 (s, 3H).

EXAMPLE 3(3)

[0281]2-((2E)-3-(5-(5-methyl-2-(4-ethylphenyl)oxazol-4-ylmethyl)furan-2-yl)-2-propenylthio)aceticacid

[0282] TLC: Rf 0.65 (chloroform:methanol=5:1);

[0283] NMR (CDCl₃): δ7.89 (d, J=8.0 Hz, 2H), 7.25 (d, J=8.0 Hz, 2H),6.25 (d, J=16.0 Hz, 1H), 6.13 (d, J=3.2 Hz, 1H), 6.05 (d, J=3.2 Hz, 1H),6.00 (dt, J=16.0, 7.5 Hz,1H), 3.90 (s, 2H), 3.37 (d, J=7.5 Hz, 2H), 3.20(s, 2H), 2.68 (q, J=7.6 Hz, 2H), 2.32 (s, 3H), 1.25 (t, J=7.6 Hz, 3H).

EXAMPLE 3(4)

[0284]2-((2E)-3-(5-(5-methyl-2-phenyloxazol-4-ylmethyl)thiophen-2-yl)-2-propenylthio)aceticacid

[0285] TLC: Rf 0.39 (chloroform:methanol=10:1);

[0286] NMR (CDCl₃): δ8.00−7.97 (m, 2H), 7.44−7.40 (m, 3H), 6.74 (d, J3.6 Hz, 1H), 6.73 (d, J=3.6 Hz, 1H), 6.52 (br.d, J=15.6 Hz, 1H), 5.84(dt, J=15.6, 7.5 Hz, 1H), 4.02 (s, 2H), 3.35 (br.d, J=7.5 Hz, 2H), 3.18(s, 2H), 2.34 (s, 3H).

EXAMPLE 3(5)

[0287] 2-methyl-2-((2E)-3-(5-(5-methyl-2-(1,3-dioxaindan-5-yl)oxazol-4-ylmethyl)furan-2-yl)-2-propenylthio)propanoic acid

[0288] TLC: Rf 0.62 (water:methanol:chloroform=1:10:100);

[0289] NMR (CDCl₃): δ7.53 (dd, J=8.0, 2.0 Hz, 1H), 7.44 (d, J=2.0 Hz,1H), 6.84 (d, J=8.0 Hz, 1H), 6.28 (d, J=15.5 Hz, 1H), 6.09 (d, J=3.0 Hz,1H), 6.06 (dt, J=15.5, 7.0 Hz, 1H), 6.03 (d, J=3.0 Hz, 1 H), 6.00 (s,2H), 3.86 (s, 2H), 3.43 (d, J=7.0 Hz, 2H), 2.27 (s, 3H), 1.54 (s, 6H).

EXAMPLE 3(6)

[0290] 1-((2E)-3-(5-(5-methyl-2-(1,3-dioxaindan-5-yl) oxazol-4-ylmethyl)furan-2-yl)-2-propenylthio)cyclobutanecarboxylic acid

[0291] TLC: Rf 0.63 (water:methanol:chloroform=1:10:100);

[0292] NMR (CDCl₃): δ7.52 (dd, J=8.0, 2.0 Hz, 1H), 7.44 (d, J=2.0 Hz,1H), 6.84 (d, J=8.0 Hz, 1H), 6.26 (d, J=15.5 Hz, 1H), 6.09 (d, J=3.0 Hz,1H), 6.07 (dt, J=15.5, 7.0 Hz, 1H), 6.03 (d, J=3.0 Hz, 1 H), 6.00 (s,2H), 3.86 (s, 2H), 3.36 (d, J=7.0 Hz, 2H), 2.68 (m, 2H), 2.40−1.80 (m,4H), 2.27 (s, 3H).

EXAMPLE 3(7)

[0293]2-((2E)-3-(5-(5-methyl-2-(4-dimethylaminophenyl)oxazol-4-ylmethyl)furan-2-yl)-2-propenylthio)aceticacid

[0294] TLC: Rf 0.43 (chloroform:methanol=10:1);

[0295] NMR (CDCl₃ with 2 drops of CD₃OD): δ7.83 (m, 2H), 6.71 (m, 2H),6.26 (d, J=15.6 Hz, 1H), 6.13 (d, J=3.0 Hz, 1H), 6.04 (d, J=3.0 Hz, 1H),6.02 (dt, J=15.6, 7.5 Hz, 1H), 3.85 (s, 2H), 3.37 (d, J 7.5 Hz, 2H),3.18 (s, 2H), 3.01 (s, 6H), 2.29 (brs, 3H).

EXAMPLE 3(8)

[0296]2-((2E)-3-(5-(5-methyl-2-(2-dimethylaminopyridin-5-yl)oxazol-4-ylmethyl)furan-2-yl)-2-propenylthio)acetic acid

[0297] TLC: Rf 0.44 (chloroform methanol=7:1);

[0298] NMR (CDCl₃): δ8.73 (dd, J=2.4, 0.8 Hz, 1H), 7.99 (dd, J=9.0, 2.4Hz, 1H), 6.53 (dd, J=9.0, 0.8 Hz, 1H), 6.27 (d, J 15.6 Hz, 1H), 6.13 (d,J=3.4 Hz, 1H), 6.06 (d, J=3.4 Hz, 1H), 5.99 (d, J 15.6, 7.2 Hz, 1H),3.85 (s, 2H), 3.39 (d, J=7.2 Hz, 2H), 3.17 (s, 2H), 3.15 (s, 6H), 2.29(s, 3H).

EXAMPLE 3(9)

[0299]2-methyl-2-((2E)-3-(5-(5-methyl-2-(4-dimethylaminophenyl)oxazol-4-ylmethyl)furan-2-yl)-2-propenylthio)propanoicacid

[0300] TLC: Rf 0.49 (chloroform:methanol=10:1);

[0301] NMR (CDCl₃): δ7.84 (m, 2H), 6.70 (m, 2H), 6.26 (d, J=15.6 Hz,1H), 6.08 (d, J=3.0 Hz, 1H), 6.06 (dt, J=15.6, 7.0 Hz, 1H), 6.01 (d,J=3.0 Hz, 1H), 3.86 (s, 2H), 3.40 (d, J=7.0 Hz, 2H), 3.01 (s, 6H), 2.27(s, 3H), 1.54 (s, 6H).

EXAMPLE 3 (10)

[0302]1-((2E)-3-(5-(5-methyl-2-(4-dimethylaminophenyl)oxazol-4-ylmethyl)furan-2-yl)-2-propenylthio)cyclobutanecarboxylicacid

[0303] TLC: Rf 0.49 (chloroform:methanol=10:1);

[0304] NMR (CDCl₃): δ7.85 (m, 2H), 6.70 (m, 2H), 6.24 (d, J=15.8 Hz,1H), 6.09 (d, J=3.2 Hz,1H), 6.07 (m,1H), 6.02 (d, J=3.2 Hz,1H), 3.87 (s,2H), 3.33 (d, J=7.0 Hz, 2H), 3.01 (s, 6H), 2.78−2.56 (m, 2H), 2.30−2.08(m, 3H), 2.27 (s, 3H), 2.02−1.80 (m, 1H).

EXAMPLE 3(11)

[0305] 2-methyl-2-((2E)-3-(5-(5-methyl-2-(4-dimethylaminopyridin-5-yl)oxazol-4-ylmethyl)furan-2-yl)-2-propenylthio)propanoic acid

[0306] TLC: Rf 0.53 (chloroform:methanol=7:1);

[0307] NMR (CDCl₃): δ8.74 (d, J=2.4 Hz, 1H), 8.01 (dd, J=9.0, 2.4 Hz,1H), 6.52 (d, J=9.0 Hz,1H), 6.26 (d, J=15.6 Hz,1H), 6.15-5.98 (m, 3H),3.85 (s, 2H), 3.44 (d, J=7.2 Hz, 2H), 3.12 (s, 6H), 2.26 (s, 3H), 1.55(s, 6H).

EXAMPLE 3(12)

[0308]1-((2E)-3-(5-(5-methyl-2-(4-dimethylaminopyridin-5-yl)oxazol-4-ylmethyl)furan-2-yl)-2-propenylthio)cyclobutanecarboxylicacid

[0309] TLC: Rf 0.54 (chloroform:methanol=7:1);

[0310] NMR (CDCl₃): δ8.74 (d, J=2.4 Hz, 1H), 8.02 (dd, J 9.0, 2.4 Hz,1H), 6.52 (d, J=9.0Hz, 1H), 6.26 (d, J=15.6Hz, 1H), 6.17-6.00 (m, 3H),3.85 (s, 2H), 3.36 (d, J=7.0 Hz, 2H), 3.13 (s, 6H), 2.82−2.56 (m, 2H),2.35−2.10 (m, 6H), 2.02−1.77 (m,1H).

EXAMPLE 4

[0311]2-((2E)-3-(5-(5-methyl-2-(1,3-dioxaindan-5-yl)oxazol-4-ylmethyl)furan-2-yl)-2-propenylsulfinyl)aceticacid

[0312] A aqueous solution (100 ml) of OXONE (trade mark) (891 mg) wasadded dropwise to a solution of the compound prepared in Example 3(2)(1.0 g) in tetrahydrofuran (200 ml) over a period of 30 minutes at −2˜3°C., and the resultant solution was stirred for 10 minutes at 0° C. Icewater was added to the reaction solution, and the resultant solution wasextracted with ethyl acetate, and the extract was washed with water anda saturated aqueous solution of sodium chloride, dried over anhydrousmagnesium sulfate, and concentrated. The residue was purified by silicagel column chromatography (chloroform:methanol=50:1→10:1) to give thetitle compound (750 mg) having the following physical data.

[0313] TLC: Rf 0.24 (water:methanol:chloroform=1:10:50);

[0314] NMR (CDCl₃): δ7.52 (dd, J=8.0, 1.5 Hz, 1H), 7.43 (d, J=1.5 Hz,1H), 6.85 (d, J=8.0 Hz, 1H), 6.45 (d, J=15.5 Hz, 1H), 6.22 (d, J=3.5 Hz,1H), 6.05 (d, J=3.5 Hz, 1H), 6.04 (dt, J=15.5, 8.0 Hz, 1H), 6.01 (s,2H), 3.88 (s, 2H), 3.85−3.75 (m, 2H), 3.81 (d, J 14.5 Hz, 1H), 3.66 (d,J 14.5 Hz, 1H), 2.31 (s, 3H).

EXAMPLE 4(1)

[0315]2-((2E)-3-(5-(5-methyl-2-phenyloxazol-4-ylmethyl)furan-2-yl)-2-propenylsulfinyl)aceticacid

[0316] The compound having the following physical data was obtained bythe same procedure as Example 4, using the compound prepared in Example3.

[0317] TLC: Rf 0.11 (water:methanol:chloroform=1:10:50);

[0318] NMR (CDCl₃): δ9.30 (br., 1H), 7.98 (m, 2H), 7.50-7.35 (m, 3H),6.45 (d, J=15.5 Hz, 1H), 6.21 (d, J=3.0 Hz, 1H), 6.06 (d, J=3.0 Hz, 1H),6.05 (dt, J=15.5, 8.0 Hz, 1H), 3.91 (s, 2H), 3.85 (dd, J=12.5, 8.0 Hz,1H), 3.82 (d, J=14.0 Hz, 1H), 3.73 (dd, J=12.5, 8.0 Hz, 1H), 3.68 (d,J=14.0 Hz, 1H), 2.33 (s, 3H).

EXAMPLE 5

[0319]2-((2E)-3-(5-(5-methyl-2-(1,3-dioxaindan-5-yl)oxazol-4-ylmethyl)furan-2-yl)-2-propenylsulfonyl)aceticacid

[0320] A aqueous solution (5 ml) of OXONE (trade mark) (864 mg) wasadded to a solution of the compound prepared in Example 4 (503 mg) intetrahydrofuran (10 ml) at 0° C., and the resultant solution was stirredfor 4 hours at room temperature. Cold water was added to the reactionsolution, and the resultant solution was extracted with ethyl acetate,and the extract was washed with water and a saturated aqueous solutionof sodium chloride, dried over anhydrous magnesium sulfate, andconcentrated. The residue was washed with a mixed solution ofchloroform/methanol (20:1) to give the title compound (350 mg) havingthe following physical data.

[0321] TLC: Rf 0.61 (chloroform:methanol:acetic acid=50:20:1);

[0322] NMR (CD₃OD+10 drops of CDCl₃): δ7.49 (dd, J=8.0, 1.6 Hz, 1H),7.37 (d, J=1.6 Hz, 1H), 6.89 (d, J=8.0 Hz, 1H), 6.58 (d, J=15.6 Hz, 1H),6.32 (d, J=3.2 Hz, 1H), 6.12 (d, J=3.2 Hz, 1H ), 5.96-6.14 (m, 3H), 4.14(d, J=7.8 Hz, 2H), 4.08 (s, 2H), 3.88 (s, 2H), 2.32 (s, 3H).

EXAMPLE 5(1)

[0323]2-((2E)-3-(5-(5-methyl-2-phenyloxazol-4-ylmethyl)furan-2-yl)-2-propenylsulfonyl)aceticacid

[0324] The compound having the following physical data was obtained bythe same procedure as Example 5, using the compound prepared in Example4(1).

[0325] TLC: Rf 0.34 (water:methanol:chloroform=1:10:50);

[0326] NMR (DMSO-d6): δ7.91 (m, 2H), 7.60−7.40 (m, 3H), 6.58 (d, J=15.5Hz, 1H), 6.43 (d, J=3.0 Hz, 1H), 6.19 (d, J=3.0 Hz, 1H), 5.95 (m, 1H),4.24 (m, 2H), 3.95 (m, 2H), 3.92 (s, 2H), 2.35 (s, 3H).

REFERENCE EXAMPLE 7

[0327] 2-(5-methyl-2-phenyloxazol-4-yl methyl)furan

[0328] The title compound (5.27 g) having the following physical datawas obtained by the same procedure as Reference Example 4, using4-chloromethyl-5-methyl-2-phenyloxazole (8.31 g) and2-(n-butylstannylfuran (15.7 g).

[0329] TLC: Rf 0.68 (ethyl acetate:hexane=1:4);

[0330] NMR (CDCl₃): δ8.02−7.97 (m, 2H), 7.44−7.40 (m, 3H), 7.35−7.34 (m,1H), 6.32−6.30 (m, 1H), 6.12−6.10 (m, 1H), 3.91 (s, 2H), 2.29 (s, 3H).

REFERENCE EXAMPLE 8

[0331] 2-bromo-5-(5-methyl-2-phenyloxazol-4-ylmethyl)furan

[0332] N-bromosuccinimide (2.8 g) and 2,2′-azobisisobutyronitrile (10mg) were added to a solution of the compound prepared in ReferenceExample 7 (2.0 g) in benzene (40 ml), and the resultant solution wasstirred for 5 hours at room temperature. The insoluble material in thereaction solution was filtered out. The filtrate was diluted with ethylacetate, and the resultant solution was washed with a saturated aqueoussolution of sodium hydrogencarbonate and a saturated aqueous solution ofsodium chloride, dried over anhydrous magnesium sulfate, andconcentrated. The residue was purified by silica gel columnchromatography (ethyl acetate:hexane=1:20) to give the title compound(267 mg) having the following physical data.

[0333] TLC: Rf 0.68 (ethyl acetate:toluene=1:4);

[0334] NMR (CDCl₃): δ8.01−7.96 (m, 2H), 7.45−7.40(m, 3H), 6.21 (d, J=3.2Hz, 1H), 3.87 (br.s, 2H), 2.31 (s, 3H).

REFERENCE EXAMPLE 9

[0335]3-(5-(5-methyl-2-phenyloxazol-4-ylmethyl)furan-2-yl)-2-propyn-1-ol

[0336] The mixture of the compound prepared in Reference Example 8 (260mg), propargyl alcohol (94 μl), tetrakis(triphenylphosphine)palladium(47 mg), copper bromide (20 mg), lithium bromide (70 mg) and piperidine(1 ml) was stirred for 30 minutes at 90° C. After cooling to roomtemperature, the reaction mixture was concentrated. The residue waspurified by silica gel column chromatography (ethyl acetate:hexane=1:2)to give the title compound (126 mg) having the following physical data.

[0337] TLC: Rf 0.46 (ethyl acetate:hexane=1:1);

[0338] NMR (CDCl₃): δ8.01−7.96 (m, 2H), 7.45−7.40(m, 3H), 6.63 (d, J=3.2Hz, 1H), 6.10 (d, J=3.2 Hz, 1H), 4.50 (s, 2H), 3.88 (s, 2H), 2.30 (s,3H).

EXAMPLE 6

[0339]2-(3-(5-(5-methyl-2-phenyloxazol-4-ylmethyl)furan-2-yl)-2-propynylthio)aceticacid.methyl ester

[0340] The title compound having the following physical data wasobtained by the same procedure as Reference Example 9, using thecompound prepared in Example 9.

[0341] TLC: Rf 0.35 (ethyl acetate:hexane=1:3);

[0342] NMR (CDCl₃): δ8.01−7.96 (m, 2H), 7.44−7.40 (m, 3H), 6.49 (d,J=3.4 Hz, 1H), 6.10−6.08 (m, 1H), 3.88 (br.s, 1H), 3.74 (s, 3H), 3.65(s, 2H), 3.45 (s, 2H), 2.31 (s, 3H).

EXAMPLE 7

[0343] 2-(3-(5-(5-methyl-2-phenyloxazol-4-ylmethyl)furan-2-yl)-2-propynylthio)acetic acid

[0344] The title compound having the following physical data wasobtained by the same procedure as Reference Example 3, using thecompound prepared in Example 6.

[0345] TLC: Rf 0.25 (chloroform:methanol=10:1);

[0346] NMR (CDCl₃): δ8.30−7.90 (br.s, 1H), 7.98−7.95 (m, 2H), 7.45−7.39(m, 3H), 6.48 (d, J=3.3 Hz, 1H), 6.08 (d, J=3.3 Hz, 1H), 3.89 (s, 2H),3.65 (s, 2H), 3.46 (s, 2H), 2.30 (s, 3H).

[FORMULATION EXAMPLE] FORMULATION EXAMPLE 1

[0347] The following compounds were admixed in conventional method andpunched out to obtain 100 tablets each containing 100 mg of activeingredient.

[0348] 2-((2E)-3-(5-(5-methyl-2-phenyloxazol -4-ylmethyl)furan-2-yl)-2-propenylthio)acetic acid 10.0 g Cellulose calcium glycolate(disintegrating agent) 0.2 g Magnesium stearate (lubricating agent) 0.1g Micro crystalline cellulose 9.7 g

FORMULATION EXAMPLE 2

[0349] The following components were admixed in a conventional method,and the solution was sterilized in a conventional method, placed 5 mlportions into ampoules and freeze-dried in a conventional method toobtain 100 ampoules each containing 20 mg of active ingredient.

[0350] 2-((2E)-3-(5-(5-methyl-2-phenyloxazol-4-ylmethyl)furan-2-yl)-2-propenylthio)acetic acid 2.0 g Mannit  5.0 gDistilled water  500 ml

[0351]

1 3 1 85 DNA Artificial Sequence Enhancer sequence including Gal4protein response sequence 1 tcgacggagt actgtcctcc gcgacggagt actgtcctccgcgacggagt actgtcctcc 60 gcgacggagt actgtcctcc gagct 85 2 9 PRT UnknownNuclear localization signal derived from SV40 T-antigen 2 Ala Pro LysLys Lys Arg Lys Val Gly 1 5 3 9 PRT Influenza virus misc_featurehemagglutinin epitope 3 Tyr Pro Tyr Asp Val Pro Asp Tyr Ala 1 5

1. A compound of formula (I)

(wherein R¹ independently, is hydrogen, C1˜8 alkyl, halogen, C1˜4alkoxy, C1˜4 alkoxy, C1˜4 alkylthio, nitro, NR⁴R⁵ (in which R⁴ and R⁵each independently, is C1˜4 alkyl.), cyano, trifluoromethyl,trifluoromethyloxy, carbocyclic ring or hetero ring (carbocyclic ringand hetero ring are optionally substituted by group selected from C1˜4alkyl, C1˜4 alkoxy, halogen or trifluoromethyl.), R² is hydrogen, C1˜8alkyl, halogen, C1˜4 alkoxy, C1˜4 alkylthio, nitro, NR⁴R⁵ (in which R⁴and R⁵ each independently, is C1˜4 alkyl,)4 cyano, trifluoromethyl ortrifluoromethyloxy, R³ is hydrogen or C1˜4 alkyl, X¹ is —N— or —CH—, X²and Y each independently, is —O—, —S— or —NR⁶— (in which R⁶ is hydrogenor C1˜4 alkyl.), Z is —O— or —S(O)_(p)— (in which p is 0, 1 or 2), R⁷and R⁸ each independently, is hydrogen or C1˜4 alkyl, or R⁷ and R⁸ takentogether with carbon atom to which is attached represents C3˜7cycloalkylene,

is carbocyclic ring or hetero ring,

is double bond or triple bond, m and n each independently, is 1˜3.), anon-toxic salt thereof, or a hydrate thereof
 2. A compound according toclaim 1, wherein X¹ is —N—, X² is —O—, or —S—, a non-toxic salt thereof,or a hydrate thereof.
 3. A compound according to claim 1, wherein Y is—O—, —S—, a non-toxic salt thereof, or a hydrate thereof.
 4. A compoundaccording to claim 1, wherein

is double bond, a non-toxic salt thereof, or a hydrate thereof.
 5. Acompound according to claim 1, wherein X¹ is —N—, X² is —O—, Y is —O—,

is double bond, a non-toxic salt thereof, or a hydrate thereof.
 6. Acompound according to claim 1, which is (1)2-((2E)-3-(5-(5-methyl-2-phenyloxazol-4-ylmethyl)furan-2-yl)-2-propenylthio)aceticacid.methyl ester, (2)2-((2E)-3-(5-(5-methyl-2-(4-methylphenyl)oxazol-4-ylmethyl)furan-2-yl)-2-propenylthio)aceticacid.methyl ester, (3)2-((2E)-3-(5-(5-methyl-2-(1,3-dioxaindan-5-yl)oxazol-4-ylmethyl)furan-2-yl)-2-propenylthio)aceticacid.methyl ester, (4)2-((2E)-3-(5-(5-methyl-2-(4-ethylphenyl)oxazol-4-ylmethyl)furan-2-yl)-2-propenylthio)acetic acid.methyl ester, (5)2-((2E)-3-(5-(5-methyl-2-phenyloxazol-4-ylmethyl)thiophen-2-yl)-2-propenylthio)aceticacid.methyl ester, (6)2-methyl-2-((2E)-3-(5-(5-methyl-2-(1,3-dioxaindan-5-yl)oxazol-4-ylmethyl)furan-2-yl)-2-propenylthio)propanoicacid.ethyl ester, (7)1-((2E)-3-(5-(5-methyl-2-(1,3-dioxaindan-5-yl)oxazol-4-ylmethyl)furan-2-yl)-2-propenylthio)cyclobutanecarboxylic acid.ethyl ester, (8)2-((2E)-3-(5-(5-methyl-2-(4-dimethylaminophenyl)oxazol-4-ylmethyl)furan-2-yl)-2-propenylthio)aceticacid.methyl ester, (9)2-((2E)-3-(5-(5-methyl-2-(2-dimethylaminopyridin-5-yl)oxazol-4-ylmethyl)furan-2-yl)-2-propenylthio)aceticacid.methyl ester, (10)2-methyl-2-((2E)-3-(5-(5-methyl-2-(4-dimethylaminophenyl)oxazol-4-ylmethyl)furan-2-yl)-2-propenylthio)propanoicacid.ethyl ester (11)1-((2E)-3-(5-(5-methyl-2-(4-dimethylaminophenyl)oxazol-4-ylmethyl)furan-2-yl)-2-propenylthio)cyclobutanecarboxylicacid.ethyl ester (12)2-methyl-2-((2E)-3-(5-(5-methyl-2-(4-dimethylaminopyridin-5-yl)oxazol-4-ylmethyl)furan-2-yl)-2-propenylthio)propanoicacid.ethyl ester (13)1-((2E)-3-(5-(5-methyl-2-(4-dimethylaminopyridin-5-yl)oxazol-4-ylmethyl)furan-2-yl)-2-propenylthio)cyclobutanecarboxylicacid.ethyl ester (14)2-((2E)-3-(5-(5-methyl-2-phenyloxazol-4-ylmethyl)furan-2-yl)-2-propenylthio)aceticacid, (15) 2-((2E) -3-(5-(5-methyl-2-(4-methylphenyl)oxazol-4-ylmethyl)furan-2-yl)-2-propenylthio)acetic acid, (16)2-((2E)-3-(5-(5-methyl-2-(1,3-dioxaindan-5-yl)oxazol-4-ylmethyl)furan-2-yl)-2-propenylthio)acetic acid, (17)2-((2E)-3-(5-(5-methyl-2-(4-ethylphenyl)oxazol-4-ylmethyl)furan-2-yl)-2-propenylthio)aceticacid, (18)2-((2E)-3-(5-(5-methyl-2-phenyloxazol-4-ylmethyl)thiophen-2-yl)-2-propenylthio)aceticacid, (19) 2-methyl-2-((2E)-3-(5-(5-methyl-2-(1,3-dioxaindan-5-yl)oxazol-4-ylmethyl)furan-2-yl)-2-propenylthio)propanoic acid, (20)1-((2E)-3-(5-(5-methyl-2-(1,3-dioxaindan-5-yl)oxazol-4-ylmethyl)furan-2-yl)-2-propenylthio)cyclobutanecarboxylic acid, (21)2-((2E)-3-(5-(5-methyl-2-(4-dimethylaminophenyl)oxazol-4-ylmethyl)furan-2-yl)-2-propenylthio)aceticacid, (22)2-((2E)-3-(5-(5-methyl-2-(2-dimethylaminopyridin-5-yl)oxazol-4-ylmethyl)furan-2-yl)-2-propenylthio)aceticacid, (23)2-methyl-2-((2E)-3-(5-(5-methyl-2-(4-dimethylaminophenyl)oxazol-4-ylmethyl)furan-2-yl)-2-propenylthio)propanoicacid, (24)1-((2E)-3-(5-(5-methyl-2-(4-dimethylaminophenyl)oxazol-4-ylmethyl)furan-2-yl)-2-propenylthio)cyclobutanecarboxylicacid, (25)2-methyl-2-((2E)-3-(5-(5-methyl-2-(4-dimethylaminopyridin-5-yl)oxazol-4-ylmethyl)furan-2-yl)-2-propenylthio)propanoicacid, (26)1-((2E)-3-(5-(5-methyl-2-(4-dimethylaminopyridin-5-yl)oxazol-4-ylmethyl)furan-2-yl)-2-propenylthio)cyclobutanecarboxylicacid, (27) 2-((2E) -3-(5-(5-methyl-2-(1,3-dioxaindan-5-yl)oxazol-4-ylmethyl)furan-2-yl)-2-propenylsulfinyl)acetic acid, (28)2-((2E)-3-(5-(5-methyl-2-phenyloxazol-4-ylmethyl)furan-2-yl)-2-propenylsulfinyl)aceticacid, (29) 2-((2E)-3-(5-(5-methyl-2-(1,3-dioxaindan-5-yl)oxazol-4-ylmethyl)furan-2-yl)-2-propenylsulfonyl)acetic acid, (30)2-((2E)-3-(5-(5-methyl-2-phenyloxazol-4-ylmethyl)furan-2-yl)-2-propenylsulfonyl)aceticacid, (31)2-(3-(5-(5-methyl-2-phenyloxazol-4-ylmethyl)furan-2-yl)-2-propynylthio)aceticacid.methyl ester, or (32) 2-(3-(5-(5-methyl-2-phenyloxazol-4-ylmethyl)furan-2-yl)-2-propynylthio)acetic acid, or a non-toxic saltthereof, or a hydrate thereof.
 7. A peroxisome proliferator activatedreceptor regulator comprising a compound of formula (I) described inclaim 1, a non-toxic salt thereof or a hydrate thereof as activeingredient.
 8. A peroxisome proliferator activated receptor regulatoraccording to claim 7, whose activity is PPARα agonist and/or PPARγagonist, comprising a compound of formula (I) described in claim 1, anon-toxic salt thereof or a hydrate thereof as active ingredient.
 9. Ahypoglycemic agent, hypolipidemic agent, preventive and/or a remedy fordiseases associated with metabolic disorders (diabetes, obesity,syndrome X, hypercholesterolemia, hyperlipoproteinemia etc.),hyperlipidemia, atherosclerosis, hypertension, circulatory diseases,overeating and coronary heart diseases, an HDL cholesterol-elevatingagent, an LDL cholesterol and/or VLDL cholesterol-lowering agent, anagent for relief from risk factor of diabetes or syndrome X comprising acompound of the formula (I) described in claim 1, a non-toxic acidthereof or a hydrate thereof as active ingredient.